Substituted Pyrrole Derivatives and Their Use as HMG-CO Inhibitors

ABSTRACT

The present invention relates to substituted pyrrole derivatives, which can be used as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors. Compounds disclosed herein can function as cholesterol lowering agents and can be used for the treatment of cholesterol-related diseases and related symptoms. Processes for the preparation of disclosed compounds are provided, as well as pharmaceutical compositions containing the disclosed compounds, and methods of treating cholesterol-related diseases and related symptoms.

FIELD OF THE INVENTION

The present invention relates to substituted pyrrole derivatives, whichcan be used as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductaseinhibitors.

Compounds disclosed herein can function as cholesterol lowering agentsand can be used for the treatment of cholesterol-related diseases andrelated symptoms. Processes for the preparation of disclosed compoundsare provided, as well as pharmaceutical compositions containing thedisclosed compounds, and methods of treating cholesterol-relateddiseases and related symptoms.

BACKGROUND OF THE INVENTION

Cardiovascular disease and its associated maladies, dysfunctions andcomplications are a principal cause of disability and the chief cause ofdeath. One specific factor significantly contributing to thispathophysiologic process is atherosclerosis, which has been generallyrecognized as the leading health care problem both with respect tomortality and health care costs.

Atherosclerosis is characterized by the deposition of fatty substances,primarily cholesterol, resulting in plaque formation on the innersurface of the arterial wall and degenerative change to the arteries.

It is now well established that cardiovascular disorders includingmyocardial infarction, coronary heart disease, hypertension andhypotension, cerebrovascular disorders including stroke, cerebralthrombosis and memory loss due to stroke; peripheral vascular diseaseand intestinal infarction are caused by blockage of arteries andarterioles by atherosclerotic plaque. Atherosclerotic plaque formationis multi-factorial in its production. Hypercholesterolemia, especiallyelevated levels of low-density lipoprotein cholesterol (LDL), is animportant risk factor for atherosclerosis and arteriosclerosis andassociated diseases.

The HMG-CoA reductase inhibitors (statins) have been used in reducingblood levels of LDL cholesterol. Cholesterol is produced via themevalonic acid pathway. Reducing the formation of mevalonic acid, aprecursor to cholesterol, leads to a corresponding decrease in hepaticcholesterol biosynthesis with a reduction in the cellular pool ofcholesterol.

U.S. Pat. No. 4,681,893 assigned to Wamer-Lambert, discloses certaintrans-6-[2-(3-, or 4-carbaoxamido-substitutedpyrrole-1-yl)alkyl]-4-hydroxypyran-2-ones and the correspondingring-opened hydroxy acids derived therefrom, includingtrans(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2,1-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide,which are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase(HMG-CoA), an important coenzyme catalyzing the intracellular synthesisof cholesterol.

U.S. Pat. No. 5,273,995 assigned to Warner Lambert, relates to theoptically pure (R, R) form of the ring-opened acid oftrans-5-(4-fluorophenyl)-2-(1-methylethyl-N,4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamidethat is [R—(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid, pharmaceutically acceptable salts thereof, specifically itscalcium salt (Atorvastatin, Lipitor®), which is currently being used forthe treatment of hypercholesterolemia.

U.S. Pat. No. 5,385,929 discloses certain phenyl hydroxy derivatives ofthe compounds disclosed in U.S. Pat. No. 5,273,995, and that such phenylhydroxy derivatives are also active as the inhibitors of thebiosynthesis of cholesterol.

SUMMARY OF THE INVENTION

The present invention relates to substituted pyrrole derivatives, whichcan be used as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductaseinhibitors, and processes for the synthesis of these compounds. Thesecompounds show utility in inhibiting HMG-CoA reductase, among the keyrate limiting steps in the biosynthetic pathway of cholesterolformation. Therefore, these compounds hold promise for the treatment ofhypercholesterolemia and hyperlipidemia

Pharmaceutically acceptable salts, pharmaceutically acceptable solvates,tautomers, racemates, polymorphs, pure enantiomers, diastereoisomers,metabolites, prodrugs or N-oxides of these compounds having the sametype of activity are also provided.

Pharmaceutical composition containing the compounds, and which may alsocontain pharmaceutically acceptable carriers or diluents, which can beused for the treatment of cholesterol-related disease or relatedsymptoms thereof are also provided.

Other aspects will be set forth in the accompanying description whichfollows and in the part will be apparent from the description or may belearnt by the practice of the invention.

In accordance with another aspect, there is provided a method fortreating a mammal suffering from cholesterol related disease, diabetesand related disease, cerebrovascular disease or cardiovascular disease,comprising administering to a mammal a therapeutically effective amountof compounds disclosed herein.

The compounds of the present invention can be used for treatingarteriosclerosis, atherosclerosis, hypercholesterolemia, hyperlipidemia,hyperlipoproteinemia, hypertriglyceridemia, hypertension, stroke,ischemia, endothelium dysfunction, peripheral vascular disease,peripheral arterial disease, coronary heart disease, myocardialinfarction, cerebral infarction, myocardial microvascular disease,dementia, Alzheimer's disease, osteoporosis and/or osteopenia, angina orresterosis.

In accordance with one aspect, there is provided a compound having thestructure of Formula I,

its pharmaceutically acceptable salts, pharmaceutically acceptablesolvates, prodrugs, metabolites, polymorphs, tautomers, racemates, pureenantiomers, diastereoisomers or N-oxides wherein

R₁ can be C₁-C₆, C₃-C₆, or optionally substituted phenyl (wherein up tothree substituents are independently selected from halogens, C₁-C₆alkyl, cyano, or C₁-C₃ perfluoroalkyl);R₂ can be optionally substituted phenyl (wherein up to threesubstituents are independently selected from cyano, acetyl, oroptionally substituted amino, wherein up to two amino substituents areindependently selected from C₁-C₆ alkyl, C₃-C₆ cycloalkyl, acetyl, orsulfonamide);R₃ can be optionally substituted C₁-C₆ alkyl or C₃-C₆ cycloalkyl(wherein substituents are independently selected from halogens,hydroxyl, C₁-C₃ alkoxy and protected hydroxyl);R₃ can also be —NR₈R₉, wherein R₈ and R₉ are optionally substitutedC₁-C₆ alkyl (wherein the optional substituent(s) is/are selected fromhalogens, hydroxy, C₁-C₃ alkoxy and protected hydroxyl);

R₄ can be

wherein R₅ and R₆ are independently hydrogen, C₁-C₆ alkyl or C₃-C₆cycloalkyl, optionally substituted aryl or aralkyl, wherein thesubstituents are selected from halogens, cyano, optionally substitutedC₁-C₆ alkyl (wherein up to two substituents are independently selectedfrom hydroxyl, protected hydroxyl, and halogen(s)), optionallysubstituted amino (wherein up to two substituents are independentlyselected from SO₂R₇, COR₇, or CONHR₇, wherein R₇ is C₁-C₆ alkyl oraryl), or acetyl, trifluoromethyl, or C₁-C₆ alkoxycarbonyl, or R₅ and R₆together form a 5-7 membered ring with one or more optional heteroatomswherein the hetero atom(s) are independently selected from nitrogen,oxygen and sulfur,or R₄ can be an optionally substituted mono-, bi- or tricyclicheterocycle having one or more hetero atom(s) wherein said heretoatom(s) is/are independently selected from oxygen, nitrogen and sulfur,and the optional substituents are independently selected from halogens,hydroxy, protected hydroxyl, C₁-C₃ alkoxy, cyano, C₁-C₃ perfluoroalkyl,C₁-C₆ alkyl or C₃-C₆ cycloalkyl, aryl or optionally substituted aralkylwherein the substituents are independently selected from halogens,hydroxy, protected hydroxyl, C₁-C₃ alkoxy, cyano, or C₁-C₃perfluoroalkyl,and the pharmaceutically acceptable salts, tautomers, racemates, pureenantiomers or diastereoisomers, and solvates of the compounds ofFormula I, with the proviso that R₂ is phenyl only when (1) R₅ or R₆ isC₃-C₆ cycloalkyl or phenyl substituted with acetyl, alkyl, cycloalkyl,hydroxyalkyl, alkylsulfonamido, acetamido or (2) when R₅ and R₆ togetherform a 5-7 membered ring with or without one or more heteroatoms whereinthe hetero atom(s) are selected from nitrogen, oxygen and sulfur or (3)when R₅ or R₆ is aralkyl optionally substituted with halogens, cyano,C₁-C₆ alkyl, C₁-C₆ halogenated alkyl or (4) when R₄ is optionallysubstituted mono-, bi- or tricyclic heterocycle having one or morehetero atom(s) (wherein the optional substituents are independentlyselected from halogens, hydroxy, protected hydroxyl, C₁-C₃ alkoxy,cyano, perfluoroalkyl of one to three carbon atoms, C₁-C₆ alkyl, C₃-C₆cycloalkyl, aryl, or optionally substituted aralkyl (wherein the aralkylsubstituents are independently selected from halogens, hydroxy,protected hydroxyl, C₁-C₃ alkoxy, cyano, or C₁-C₃ perfluoroalkyl)).

In accordance with another aspect, there are provided compounds havingthe structure of Formula Ib,

their pharmaceutically acceptable salts, pharmaceutically acceptablesolvates, tautomers, racemates, polymorphs, pure enantiomers,diastereoisomers, metabolites, prodrugs or N-oxides wherein

R₁ can be C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or optionally substitutedphenyl (wherein the substituent(s) is/are selected from halogens, C₁-C₆alkyl, cyano and C₁-C₃ perfluoroalkyl);R₂ can be optionally substituted phenyl (wherein the substituent(s)is/are selected from cyano, acetyl and optionally substituted amino);R₃ can be optionally substituted C₁-C₆ alkyl or C₃-C₆ cycloalkyl(wherein the substituent(s) is/are selected from halogens, hydroxyl,C₁-C₃ alkoxy, and protected hydroxyl); R₃ can also be —NR₆R₇ wherein R₆and R₇ are optionally substituted C₁-C₆ alkyl (wherein the optionalsubstituent(s) is/are selected from halogens, hydroxyl, C₁-C₃ alkoxy,and protected hydroxyl);R₄ can be acetyl, C₁-C₂ alkoxycarbonyl, optionally substituted C₁-C₆alkyl (wherein the substituent is hydroxy or protected hydroxyl), NHR₈[wherein R₈ is selected from alkyl, aralkyl, SO₂R₉, COR₉ or CONHR₉,CSNHR₉ (wherein R₉ is C₁-C₆ alkyl, aryl or aralkyl)];R₄ can also be —COR₁₀ (wherein R₁₀ is selected from hydroxyl and—NR₁₁R₁₂ (wherein R₁₁ and R₁₂ are independently selected from hydrogen,alkyl, aryl, C₃-C₇ cycloalkyl, heterocyclyl, aralkyl and R₁₁ and R₁₂together form 5-7 membered ring with one or more optional heteroatom(s)wherein the heteroatom(s) is/are independently selected from nitrogen,oxygen and sulphur);R₅ can be hydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, optionallysubstituted aryl or aralkyl [wherein the substituents are selected fromhalogens, cyano, optionally substituted C₁-C₆ alkyl (wherein thesubstituents are independently selected from hydroxyl, protectedhydroxyl, and halogen(s)], optionally substituted amino, acetyl,trifluoromethyl and C₁-C₆ alkoxycarbonyl.

In one particular embodiment, there are provided compounds of FormulaIb,

their pharmaceutically acceptable salts, pharmaceutically acceptablesolvates, tautomers, racemates, polymorphs, pure enantiomers,diastereoisomers, metabolites, prodrugs or N-oxides wherein

R₁, R₂, R₃ and R₅ are as defined earlier;R₄ can be NHR₈ [wherein R₈ is selected from aralkyl, CONHR₉ (wherein R₉is aralkyl); CSNHR₉ (wherein R₉ is C₁-C₆ alkyl, aryl or aralkyl)];—COR₁₀ (wherein R₁₀ is selected from hydroxyl and —NR₁₁R₁₂ (wherein R₁₁and R₁₂ are independently selected from hydrogen, alkyl, aryl, C₃-C₇cycloalkyl, aralkyl and R₁₁ and R₁₂ together form 5-7 membered ring withone or more optional heteroatom(s) wherein the heteroatom(s) is/areindependently selected from nitrogen, oxygen and sulphur);

In yet another particular embodiment, there are provided compounds ofFormula Ib,

their pharmaceutically acceptable salts, pharmaceutically acceptablesolvates, tautomers, racemates, polymorphs, pure enantiomers,diastereoisomers, metabolites, prodrugs or N-oxides wherein

R₁, R₂, R₃ and R₅ can be 4-fluorophenyl, phenyl, isopropyl and hydrogen,respectively; R₄ can be C₁-C₂ alkoxycarbonyl, optionally substitutedC₁-C₆ alkyl (wherein the substituent is hydroxy or protected hydroxyl),NHR₈ [wherein R₈ is selected from SO₂R₉, COR₉ or CONHR₉ (wherein R₉ ismethyl or phenyl)]

In accordance with further aspect, there are provided intermediateshaving the structure of Formula XIX,

whereinR₂ can be optionally substituted phenyl (wherein the substituent(s)is/are selected from cyano, acetyl and optionally substituted amino;R₃ can be optionally substituted C₁-C₆ alkyl or C₃-C₆ cycloalkyl(wherein the substituent(s) is/are selected from halogens, hydroxyl,C₁-C₃ alkoxy, and protected hydroxyl); R₃ can also be —NR₆R₇ wherein R₆and R₇ are optionally substituted C₁-C₆ alkyl (wherein the optionalsubstituent(s) is/are selected from halogens, hydroxyl, C₁-C₃ alkoxy,and protected hydroxyl).In accordance with third aspect, there are provided intermediates havingthe structure of Formula XX,

whereinR₁ can be C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or optionally substitutedphenyl (wherein the substituent(s) is/are selected from halogens, C₁-C₆alkyl, cyano and C₁-C₃ perfluoroalkyl);R₂ can be optionally substituted phenyl (wherein the substituent(s)is/are selected from cyano, acetyl and optionally substituted amino;R₃ can be optionally substituted C₁-C₆ alkyl or C₃-C₆ cycloalkyl(wherein the substituent(s) is/are selected from halogens, hydroxyl,C₁-C₃ alkoxy, and protected hydroxyl); R₃ can also be —NR₆R₇ wherein R₆and R₇ are optionally substituted C₁-C₆ alkyl (wherein the optionalsubstituent(s) is/are selected from halogens, hydroxyl, C₁-C₃ alkoxy,and protected hydroxyl).In accordance with fourth aspect, there are provided intermediateshaving the structure of Formula XXI,

whereinR₁ can be C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or optionally substitutedphenyl (wherein the substituent(s) is/are selected from halogens, C₁-C₆alkyl, cyano and C₁-C₃ perfluoroalkyl);R₂ can be optionally substituted phenyl (wherein the substituent(s)is/are selected from cyano, acetyl and optionally substituted amino;R₃ can be optionally substituted C₁-C₆ alkyl or C₃-C₆ cycloalkyl(wherein the substituent(s) is/are selected from halogens, hydroxyl,C₁-C₃ alkoxy, and protected hydroxyl); R₃ can also be —NR₆R₇ wherein R₆and R₇ are optionally substituted C₁-C₆ alkyl (wherein the optionalsubstituent(s) is/are selected from halogens, hydroxyl, C₁-C₃ alkoxy,and protected hydroxyl).In accordance with fifth aspect, there are provided intermediates havingthe structure of Formula XXII,

whereinR₁ can be C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or optionally substitutedphenyl (wherein the substituent(s) is/are selected from halogens, C₁-C₆alkyl, cyano and C₁-C₃ perfluoroalkyl);R₂ can be optionally substituted phenyl (wherein the substituent(s)is/are selected from cyano, acetyl and optionally substituted amino;R₃ can be optionally substituted C₁-C₆ alkyl or C₃-C₆ cycloalkyl(wherein the substituent(s) is/are selected from halogens, hydroxyl,C₁-C₃ alkoxy, and protected hydroxyl); R₃ can also be —NR₆R₇ wherein R₆and R₇ are optionally substituted C₁-C₆ alkyl (wherein the optionalsubstituent(s) is/are selected from halogens, hydroxyl, C₁-C₃ alkoxy,and protected hydroxyl).

As used herein the term “alkyl”, unless otherwise defined, refers tostraight or branched chain hydrocarbon of from 1 to 10 carbon atom(s).Examples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, butyl, octyl, and the like.

Alkyl may optionally be substituted with halogen, hydroxy, protectedhydroxyl, C₁-C₃ alkoxy, optionally substituted amino and C₁-C₆alkoxycarbonyl.

As used herein the term “optionally substituted amino”, unless otherwisedefined, refers to NR₁₄R₁₅ wherein R₁₄ and R₁₅ are independentlyselected from hydrogen, alkyl, aryl, aralkyl, C₃-C₇ cycloalkyl, SO₂R₁₆,COR₁₆, CONHR₁₆ and CSNHR₁₆ (wherein R₁₅ is C₁-C₆ alkyl, aryl oraralkyl).

As used herein the term “protected hydroxyl” refers to a hydroxy moietyprotected by a group R₁₇ wherein R₁₇ is selected from alkyl, cycloalkyl,aralkyl, aryl, —(CH₂)_(n)OR₁₈ (wherein R₁₈ is selected from alkyl,cycloalkyl, aralkyl, aryl and n represents an integer from 1 to 6),COR₁₉, CSR₁₉, CONHR₁₉ and CSNHR₁₉ (wherein R₁₉ is selected from alkyl,aryl, aralkyl and heterocyclyl). Examples of protected hydroxyl include,but are not limited to, —OCH₃, —OC₂H₅, —O-n-propyl, —O-1-propyl,—O-cyclopropyl, —O—CH₂OCH₃, —O-cyclopentyl, —O-cyclohexyl, —O-benzyl,—O-chlorobenzyl, —O-methoxybenzyl, —O-phenyl, —O-chlorophenyl, —O—COCH₃,—O—COC₂H₅, —O—CObenzyl, —O—COphenyl, —O—COpyridinyl, —O—CONHphenyl,—O—CONHpyridinyl, —O—CONH-octyl, —O—CSNHphenyl, and the like.

As used herein the term “aralkyl” refers to (CH₂)_(n)aryl wherein n isan integer from 1 to 6.

As used herein the term “aryl”, unless otherwise defined, refers to anaromatic radical having 6 to 14 carbon atoms. Examples of aryl include,but are not limited to, phenyl, napthyl, anthryl and biphenyl, and thelike.

As used herein the term “heterocyclyl” refers to non-aromatic, aromaticor aromatic fused with non-aromatic ring system having one or moreheteroatom (s) in either the aromatic or the non-aromatic part whereinthe said hetero atom (s) is/are selected from the group comprising ofnitrogen, sulphur and oxygen and the ring system includes mono, bi ortricyclic. Examples of heterocycles include, but not limited to,benzoxazinyl, benzthiazinyl, benzimidazolyl, benzofuranyl, carbazolyl,Indolyl, indolinyl, oxazolyl, phenoxazinyl, pyridyl and phenothiazinyl,and the like.

The said aryl or heterocyclyl may optionally be substituted with one ormore substituent(s) independently selected from halogen, hydroxy, nitro,cyano, alkyl, aryl, alkoxy, thioalkyl, cycloalkoxy, optionallysubstituted amino.

In accordance with yet another aspect, there are provided processes forthe preparation of the compounds described herein.

In accordance with another aspect, there is provided a method fortreating a mammal suffering from cholesterol related disease, diabetesand related disease, cerebrovascular disease or cardiovascular disease,comprising administering to a mammal a therapeutically effective amountof compounds disclosed herein.

The compounds of the present invention can be used for treatingarteriosclerosis, atherosclerosis, hypercholesterolemia, hyperlipidemia,hyperlipoproteinemia, hypertriglyceridemia, hypertension, stroke,ischemia, endothelium dysfunction, peripheral vascular disease,peripheral arterial disease, coronary heart disease, myocardialinfarction, cerebral infarction, myocardial microvascular disease,dementia, Alzheimer's disease, osteoporosis and/or osteopenia, angina orresterosis.

DETAILED DESCRIPTION OF THE INVENTION

The compounds described herein may be prepared by techniques well knownin the art and familiar to the average synthetic organic chemist. Inaddition, the compounds of the present invention may be prepared by thefollowing reaction sequences as depicted in Schemes I, Ia, Ib, II, IIa,III, IIIa, and IV. Further compounds which can be useful for treatmentof these diseases, and methods for making such compounds, are disclosedin copending U.S. patent application Ser. No. 10/448,770 filed 30 May,2003, entitled “Substituted Pyrrole Derivatives,” and PCT ApplicationNo. PCT/IB2004/______ filed ______ entitled “Substituted PyrroleDerivatives,” which applications are incorporated herein in theirentirety.

Scheme I

The compound of Formula XII can be prepared according to Scheme I.Accordingly, a compound of Formula II is reacted with a compound ofFormula III, wherein R₃, R₅ and R₆ are as defined earlier, to give acompound of Formula IV which on reaction with a compound of Formula V(wherein R₂ is as defined earlier) gives a compound of Formula VI, whichon treatment with a compound of Formula VII (wherein R₁ is as definedearlier) yields a compound of Formula VIII, which on further reactionwith a compound of Formula IX gives a compound of Formula X, which onhydrolysis gives a compound of Formula XI, which can then be furtherconverted to hemicalcium salt.

The reaction of a compound of Formula II with a compound of Formula IIIto give a compound of Formula IV can be carried out in a nonpolarsolvent, such as xylene or toluene. The reaction of a compound ofFormula II with a compound of Formula III can be carried out in thepresence of an organic base, such as triethylamine, pyridine or1,2-ethylenediamine. The reaction of a compound of Formula IV with analdehyde of Formula V to give a compound of Formula VI can be carriedout in a nonpolar solvent such as hexane, heptane, dichloromethane ortoluene or mixture(s) thereof. The reaction of a compound of Formula IVwith an aldehyde of Formula V can be carried out in the presence of anorganic base such as piperidine, pyridine or β-alanine and an organicacid such as glacial acetic acid or benzoic acid. The reaction of acompound of Formula VI with an aldehyde of Formula VII to give acompound of Formula VIII can be carried out in the presence of asuitable catalyst, such as sodium cyanide,3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide or3-benzyl-5-(2-hydroxyethyl)-4-methyl thiazolium chloride, in a solventfree condition or in an alcoholic solvent, such as methanol, ethanol,propanol or isopropanol. The reaction of a compound of Formula VI withan aldehyde of Formula VII can be carried out in the presence of anorganic base, such as triethylamine or pyridine.

The reaction of a compound of Formula VIII with a compound of Formula IXto give a compound of Formula X can be carried out in a nonpolarsolvent, such as xylene, toluene hexane, heptane, tetrahydrofuran, or amixture thereof in a suitable ratio. The reaction of a compound ofFormula VIII with a compound of Formula IX can be carried out in thepresence of an organic acid, such as pivalic acid or p-toluene sulfonicacid.

The conversion of a compound of Formula X to a compound of Formula XIcan be carried out in a two-step manner, involving an initialacid-catalysed cleavage of ketal, followed by base-catalysed hydrolysisof the tert-butyl ester. The acid can be a mineral acid, such ashydrochloric acid. The cleavage of ketal can be carried out by any othercleavage method known in the prior art. The base can be an organic base,such as lithium hydroxide, sodium hydroxide or potassium hydroxide.

The compound of Formula XI can be converted into its corresponding hemicalcium salt by following procedures well-known to a person ordinaryskilled in the art. The hemi calcium salts of compound of Formula XI canalso be prepared from the corresponding lactones form of Formula XI byfollowing procedures well-known in the art.

Scheme Ia

The compound of Formula XVII can be prepared according to Scheme Ia.Accordingly, a compound of Formula KM (that is, Formula X wherein R₅═Hand

prepared according to Scheme I) is hydrolyzed to give a compound ofFormula XIV which, on reduction, gives a compound of Formula XV, whichon hydrolysis gives a compound of Formula XVI, which can then be furtherconverted to hemi calcium salt.

The hydrolysis of a compound of Formula XIII to give a compound ofFormula XIV can be carried out in a polar solvent, such astetrahydrofuran, dioxane, methanol, ethanol or mixture(s) thereof. Thehydrolysis of a compound of Formula XIII can be carried out in thepresence of an inorganic base such as lithium hydroxide, sodiumhydroxide or potassium hydroxide.

The reduction of a compound of Formula XIV to give a compound of FormulaXV can be carried out in the presence of iodine and a reducing agent,such as sodium borohydride or borane dimethylsulphide in an organicsolvent, such as tetrahydrofuran, dioxane or diethylether.

The conversion of a compound of Formula XV to a compound of Formula XVIis carried out in a two-step manner, involving an initial acid-catalyzedcleavage of ketal, followed by base-catalyzed hydrolysis of thetert-butyl ester. The acid can be a mineral acid, such as hydrochloricacid. The cleavage of ketal can be carried out by any other cleavagemethod known in the prior art. The base can be an inorganic base, suchas lithium hydroxide, sodium hydroxide or potassium hydroxide.

The compound of Formula XVI can be converted into its corresponding hemicalcium salt by following procedures well-known to a person ordinaryskilled in the art. The hemi calcium salts of compound of Formula XVIcan also be prepared from the corresponding lactone form of Formula XVIby following procedures well-known in the art.

Scheme Ib

The compound of Formula XIIb can be prepared according to Scheme Ib.Accordingly, a compound of Formula II is reacted with a compound ofFormula IIIb, wherein R₃, R₄ and R₅ are as defined earlier, to give acompound of Formula IVb which on reaction with a compound of Formula V(wherein R₂ is as defined earlier) gives a compound of Formula VIb,which on treatment with a compound of Formula VII (wherein R₁ is asdefined earlier) yields a compound of Formula VIIIb, which on furtherreaction with a compound of Formula I×gives a compound of Formula Xb,which on hydrolysis gives a compound of Formula XIb, which can then befurther converted to hemicalcium salt.

The reaction of a compound of Formula II with a compound of Formula IIIbto give a compound of Formula IVb can be carried out in an aromaticsolvent, such as xylene or toluene. The reaction of a compound ofFormula II with a compound of Formula IIIb can be carried out in thepresence of an organic base, such as triethylamine, pyridine or1,2-ethylenediamine.

The reaction of a compound of Formula IVb with an aldehyde of Formula Vto give a compound of Formula VIb can be carried out in a hydrocarbonsolvent, such as hexane, heptane, or halogenated solvent, such asdichloromethane, or aromatic solvent, such as toluene, or mixturethereof. The reaction of a compound of Formula IVb with an aldehyde ofFormula V can be carried out in the presence of an organic base such aspiperidine, pyridine or β-alanine and an organic acid such as glacialacetic acid or benzoic acid.

The reaction of a compound of Formula VIb with an aldehyde of FormulaVII to give a compound of Formula VIM can be carried out in the presenceof a suitable catalyst, such as sodium cyanide,3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide or3-benzyl-5-(2-hydroxyethyl)-4-methyl thiazolium chloride, in a solventfree condition or in an alcoholic solvent, such as methanol, ethanol,propanol or isopropanol or ethers, such as dioxan or tetrahydrofuran.The reaction of a compound of Formula VIb with an aldehyde of FormulaVII can be carried out in the presence of an organic base, such astriethylamine or pyridine.

The reaction of a compound of Formula YAM with a compound of Formula IXto give a compound of Formula Xb can be carried out in a solvent, suchas xylene, toluene, hexane, heptane, tetrahydrofuran, or a mixturethereof in a suitable ratio. The reaction of a compound of Formula VIIIbwith a compound of Formula IX can be carried out in the presence of anorganic acid, such as pivalic acid or p-toluene sulfonic acid.

The conversion of a compound of Formula Xb to a compound of Formula XIbcan be carried out in a two-step manner, involving an initialacid-catalysed cleavage of ketal, followed by base-catalysed hydrolysisof the tert-butyl ester. The acid can be a mineral acid, such ashydrochloric acid. The cleavage of ketal can be carried out by any othercleavage method known in the prior art. The base can be an inorganicbase, such as lithium hydroxide, sodium hydroxide or potassiumhydroxide.

The compound of Formula XIb can be converted into its corresponding hemicalcium salt by following procedures well-known to a person ordinaryskilled in the art. The hemi calcium salts of compound of Formula XIbcan also be prepared from the corresponding lactones form of Formula XIbby following procedures well-known in the art.

Scheme II

The compound of Formula XII can also be prepared according to Scheme II.Accordingly, a compound of Formula XVIII is reacted with a compound ofFormula V to give a compound of Formula XIX (wherein R₂ and R₃ are asdefined earlier in Scheme I) which on reaction with a compound ofFormula VII (wherein R₁ is as defined earlier) gives a compound ofFormula XX, which on treatment with a compound of Formula IX yields acompound of Formula XXI, which on debenzylation gives a compound ofFormula XXII, which on

(a) conversion to corresponding acid chloride followed by reaction withan amine of Formula III (Path a) or

(b) reaction with an amine of Formula III in the presence of a couplingagent (Path b), gives a compound of Formula X, which on hydrolysis givesa compound of Formula XI, which can be further converted to hemicalciumsalt of Formula XI by following the procedure well known in the art.

The reaction of a compound of Formula XVIII with an aldehyde of FormulaV to give a compound of Formula XIX can be carried out in a nonpolarsolvent, such as xylene, toluene, heptane, hexane or dichloromethane ormixture thereof. The reaction of a compound of Formula XVIII with acompound of Formula V can be carried out in the presence of an organicbase, such as triethylamine, pyridine, piperidine or β-alanine and anorganic acid such as glacial acetic acid or benzoic acid.

The reaction of a compound of Formula XIX with an aldehyde of FormulaVII to give a compound of Formula XX can be carried out in a polarsolvent, such as an alcoholic solvent, for example, methanol, ethanol,propanol or isopropanol. The reaction of a compound of Formula XIX withan aldehyde of Formula VII can be carried out in the presence of anorganic base, such as triethylamine or pyridine. The reaction of acompound of Formula XIX with an aldehyde of Formula VII to give acompound of Formula XX can be carried out in the presence of a catalyst,such as sodium cyanide, 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazoliumbromide or 3-benzyl-5-(2-hydroxyethyl)-4-methyl thiazolium chloride.

The reaction of a compound of Formula XX with an amine of Formula IX togive a compound of Formula XXI can be carried out in the presence of anacid, such as pivalic acid and p-toluene sulfonic acid in a nonpolarsolvent such as hexane, heptane, toluene or tetrahydrofuran.

The debenzylation of a compound of Formula XXI to give a compound ofFormula XXII can be carried out in the presence of a catalyst, such aspalladium on carbon and hydrogen, in a polar solvent, such as methanol,ethanol, propanol or dioxane.

The conversion of compound of Formula XXII to its corresponding acidchloride (Path a) can be carried out with any suitable chlorinatingagent, such as oxalyl chloride, in a nonpolar solvent, such as benzene,dichloromethane, tetrahydrofuran, toluene or xylene, followed byreaction with an amine of Formula III to give a compound of Formula X,in a nonpolar solvent, such as benzene, and in the presence of anorganic base, such as triethylamine or pyridine.

Reaction of compound of Formula XXII with an amine of Formula III togive a compound of Formula X can be carried out in the presence of acoupling agent (Path b), such asO-benzotriazol-1-yl-N,N,N′,N′-tetramethyl uronium hexafluorophosphate(HBTU), bis(2-oxo-3-oxazolidinyl)phosphine (BOP),1,3-dicyclohexycarbodiimide (DCC),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBOP) or carbonyldiimidazole (CDI) in a polarsolvent, such as dimethylformamide, and an organic base, such asdiisopropylethyl amine.

The conversion of a compound of Formula X to a compound of Formula XIcan be carried out in a two-step manner, involving an initialacid-catalysed cleavage of ketal, followed by base-catalysed hydrolysisof the tert-butyl ester. The acid can be a mineral acid, such ashydrochloric acid. The cleavage of ketal can be carried out by any othercleavage method known in the prior art. The base can be an inorganicbase, for example, lithium hydroxide, sodium hydroxide or potassiumhydroxide.

The compound of Formula XI can be converted into its corresponding hemicalcium salt by following procedures well-known to a person ordinaryskilled in the art. The hemi calcium salts of compound of Formula XI canalso be prepared from the corresponding lactone form of Formula XI byfollowing procedures well-known in the art.

Scheme IIa

The compound of Formula XVIa can be prepared according to Scheme IIa.Accordingly, a compound of Formula XIIIa (that is, Formula Xa whereinR₅=H and R₄=—COOCH₃, prepared according to Scheme I) is hydrolyzed togive a compound of Formula XIVa, which on further hydrolysis gives acompound of Formula XVa, which can then be converted to disodium salt.

The conversion of compounds of Formula XIIIa to compounds of Formula XVacan be carried out in a two-step manner, involving an initialacid-catalyzed cleavage of ketal, followed by base-catalyzed hydrolysisof the methyl and tert-butyl ester. The acid can be a mineral acid, suchas hydrochloric acid. The cleavage of ketal can be carried out by anyother cleavage method known in the prior art. The base can be aninorganic base, such as lithium hydroxide, sodium hydroxide or potassiumhydroxide.

The compound of Formula XVa can be converted into its correspondingdisodium salt by following procedures well-known to a person ordinaryskilled in the art.

Scheme III

The compound of Formula XXVII can be prepared according to SchemeAmidoxime (prepared as per procedure described in J. Med. Chem., 45:944(2002) and J. Med. Chem., 29:2174 (1986)) of Formula XXIII on couplingwith a compound of Formula XXII (prepared following the steps of SchemeII) gives a compound of Formula XXIV, which on cyclisation in diglymegives a compound of Formula XXV, which on hydrolysis gives a compound ofFormula XXVI, which can be further converted to its hemi calcium salt.

The coupling of compound of Formula XXIII with a compound of FormulaXXII can be carried out in the presence of N,N′-carbonyldiimidazole inan organic solvent, such as tetrahydrofuran, dioxane or ether.

The cyclisation of compound of Formula XXIV can be carried out indiglyme to give a compound of Formula XXV.

The conversion of a compound of Formula XXV to a compound of FormulaXXVI can be carried out in a two-step manner, involving an initialacid-catalyzed cleavage of ketal, followed by base-catalyzed hydrolysisof the tert-butyl ester. The acid can be a mineral acid, such ashydrochloric acid. The cleavage of ketal can be carried out by any othercleavage method known in the prior art. The base can be an inorganicbase, for example, lithium hydroxide, sodium hydroxide or potassiumhydroxide.

The compound of Formula XXVI can be converted into its correspondinghemi calcium salt by following procedures well-known to a personordinary skilled in the art. The hemi calcium salts of compound ofFormula XXVI can also be prepared from the corresponding lactone form ofFormula XXVI by following procedures well-known in the art.

Scheme IIIa

The compound of Formula XIIIa can also be prepared according to SchemeIIIa. Accordingly, a compound of Formula XVIII is reacted with acompound of Formula V to give a compound of Formula XIX (wherein R₂ andR₃ are as defined earlier) which on reaction with a compound of FormulaVII (wherein R₁ is as defined earlier) gives a compound of Formula XX,which on treatment with a compound of Formula IX yields a compound ofFormula XXI, which on debenzylation gives a compound of Formula XXII,which on

(a) conversion to corresponding acid chloride followed by reaction withan amine of Formula IIIa (Path a) or

(b) reaction with an amine of Formula IIIa in the presence of a couplingagent (Path b) gives a compound of Formula Xa, which on hydrolysis givesa compound of Formula XIa, which can be further converted to hemicalcium salt of Formula XIa by following the procedure well known in theart.

The reaction of a compound of Formula XVIII with an aldehyde of FormulaV to give a compound of Formula XIX can be carried out in a hydrocarbonsolvent, such as hexane or heptane, or halogenated solvent, such asdichloromethane, or aromatic solvent, such as toluene or xylene, ormixture thereof. The reaction of a compound of Formula XVIII with acompound of Formula V can be carried out in the presence of an organicbase, such as triethylamine, pyridine, piperidine or β-alanine and anorganic acid such as glacial acetic acid or benzoic acid.

The reaction of a compound of Formula XIX with an aldehyde of FormulaVII to give a compound of Formula XX can be carried out in a polarsolvent, such as an alcoholic solvent, for example, methanol, ethanol,propanol or isopropanol. The reaction of a compound of Formula XIX withan aldehyde of Formula VII can be carried out in the presence of anorganic base, such as triethylamine or pyridine. The reaction of acompound of Formula XIX with an aldehyde of Formula VII to give acompound of Formula XX can be carried out in the presence of a catalyst,such as sodium cyanide, 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazoliumbromide or 3-benzyl-5-(2-hydroxyethyl)-4-methyl thiazolium chloride.

The reaction of a compound of Formula XX with an amine of Formula IX togive a compound of Formula XXI can be carried out in the presence of anacid, such as pivalic acid and p-toluene sulfonic acid in a hydrocarbonsolvent, such as hexane or heptane, or aromatic solvent, such astoluene, or ether, such as tetrahydrofuran or mixture thereof.

The debenzylation of a compound of Formula XXI to give a compound ofFormula XXII can be carried out in the presence of a catalyst, such aspalladium on carbon and hydrogen, in a polar solvent, such as alcoholicsolvent, for example, methanol, ethanol or propanol, or ether solvent,for example, dioxane.

The conversion of compound of Formula XXII to its corresponding acidchloride (Path a) can be carried out with any suitable chlorinatingagent, such as oxalyl chloride or thionyl chloride, in an aromaticsolvent, such as benzene, toluene or xylene, or halogenated solvent,such as dichloromethane, or ether, such as tetrahydrofuran, followed byreaction with an amine of Formula Ma to give a compound of Formula Xa,in an aromatic solvent, such as benzene, and in the presence of anorganic base, such as triethylamine or pyridine.

Reaction of compound of Formula XXII with an amine of Formula IIIa togive a compound of Formula Xa (path b) can be carried out in thepresence of a coupling agent, such asO-benzotriazol-1-yl-N,N,N′,N′-tetramethyl uronium hexafluorophosphate(HBTU), bis(2-oxo-3-oxazolidinyl)phosphine (BOP),1,3-dicyclohexycarbodiimide (DCC),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBOP) or carbonyldiimidazole (CDI) in a polarsolvent, such as dimethylformamide, and an organic base, such asdiisopropylethylamine.

The conversion of a compound of Formula Xa to a compound of Formula XIacan be carried out in a two-step manner, involving an initialacid-catalysed cleavage of ketal, followed by base-catalysed hydrolysisof the tert-butyl ester. The acid can be a mineral acid, such ashydrochloric acid. The cleavage of ketal can be carried out by any othercleavage method known in the prior art. The base can be an inorganicbase, for example, lithium hydroxide, sodium hydroxide or potassiumhydroxide.

The compound of Formula XIa can be converted into its corresponding hemicalcium salt by following procedures well-known to a person ordinaryskilled in the art.

The hemi calcium salts of compound of Formula XIa can also be preparedfrom the corresponding lactones form of Formula XIa by followingprocedures well-known in the art.

Scheme IV

The compound of Formula XXXI can be prepared according to Scheme IV.Accordingly, treating acid chloride of compound of Formula XXII withammonia affords a compound of Formula XXVIII, which on condensation withN,N-dimethylbenzamide dimethylketal followed by treatment with hydrazinehydrate gives a compound of Formula XXIX, which on hydrolysis gives acompound of Formula XXX, which can be further converted to its hemicalcium salt.

The reaction of compound of Formula XXII to give compound of FormulaXXVIII can be carried out in presence of a chlorinating agent, such asoxalyl chloride or thionyl chloride followed by reaction with ammonia.

The condensation of a compound of Formula XXVIII withN,N-dimethylbenzamide dimethylacetal followed by treatment withhydrazine hydrate affords compound of Formula XXIX.

The conversion of a compound of Formula XXIX to a compound of FormulaXXX can be carried out in a two-step manner, involving an initialacid-catalyzed cleavage of ketal, followed by base-catalyzed hydrolysisof the tert-butyl ester. The acid can be a mineral acid, such ashydrochloric acid. The cleavage of ketal can be carried out by any othercleavage, method known in the prior art. The base can be an inorganicbase, for example, lithium hydroxide, sodium hydroxide or potassiumhydroxide.

The compound of Formula XXX can be converted into its corresponding hemicalcium salt by following procedures well-known to a person ordinaryskilled in the art. The calcium salts of compound of Formula XXX canalso be prepared from the corresponding lactone form of Formula XXX byfollowing procedures well-known in the art.

In the above schemes, where specific reagents, such as particular bases,reducing agents, solvents, etc., are mentioned, it is to be understoodthat other bases, reducing agents, solvents, etc., known to thoseskilled in the art may be used. Similarly, the reaction temperature andduration may be adjusted according to the desired needs.

An illustrative list of particular compounds disclosed herein is givenbelow (also shown in Table I):

-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(2-acetylphenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 1)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(3-acetylphenylaraino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 2)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylphenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 3)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(2,4-dimethylphenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 4)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(cyclohexylamino)    carbonyl)]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    5)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-trifluoromethylbenzylamino)    carbonyl)]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 6)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(morpholine-4-carbonyl)-pyrrol-1-yl]-3,5-dihydroxy-heptanoic    acid (Compound No. 7)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(piperidine-1-carbonyl)-pyrrol-1-yl]-3,5-dihydroxy-heptanoic    acid (Compound No. 8)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    11)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methanesulfonylaminophenyl    amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 12)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylaminophenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    13)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-(4-cyanophenyl)-4-[(phenylamino)    carbonyl)]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    14)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-carboxyphenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    1a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-acetoxymethylphenyl)amino)    carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    2a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylthiocarbamoyl    oxymethylphenyl)amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic    acid (Compound No. 3a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-propionyloxymethyl    phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 4a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-octylcarbamoyloxymethyl    phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 5a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylacetoxymethyl    phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 6a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylcarbamoyl    oxymethyl phenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    7a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzoyloxymethyl    phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 8a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-isonicotinoyloxymethyl    phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 9a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-pyridin-4-ylcarbamoyl    oxymethyl phenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    10a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylcarbamoyl    phenyl)amino) carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 11a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-cyclohexylcarbamoyl-phenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    12a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-methylcarbamoyl)-phenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    13a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzylcarbamoyl)-phenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    14a),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(morpholine-4-carbonyl)-phenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    15),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(piperidine-1-carbonyl)-phenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    16),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzylamino    phenyl)amino) carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 17),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(1-hydroxyethyl)phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    18),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(2-hydroxyethyl)phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    19),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-hydroxypropyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 20),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methoxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 21),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-ethoxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 22),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-isopropoxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 23),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-propoxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 24),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methoxymethoxymethylphenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    25),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-cyclohexyloxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 26),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-cyclopentyloxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 27),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzyloxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 28)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-chlorobenzyloxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 29),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methoxybenzyloxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 30),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-phenoxymethylphenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    31),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-chlorophenoxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 32),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylaminophenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    33),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzoylamino    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 34),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzenesulfonylamino    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 36)-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-phenyl-nreido)-phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    37),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-methyl-ureido)-phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    38),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-benzyll-ureido)-phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    39),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-benzyl-thioureido)-phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    40),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-phenyl-thioureido)-phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    41),-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-methyl-thioureido)-phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    42),    and their pharmaceutically acceptable salts, pharmaceutically    acceptable solvates, tautomers, racemates, polymorphs, pure    enantiomers, diastereoisomers, metabolites, prodrugs or N-oxides.

An illustrative list of compounds, which can be prepared by followingSchemes III and IV is given below (also shown in Table I):

-   (3R,5R)-7-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(3-phenyl-[1,2,4]oxadiazol-5-yl)-pyrrol-1-yl]-3,5-dihydroxy-heptanoic    acid (Compound No. 9)-   (3R,5R)-7-[2-(4-Fluorophenyl0-5-isopropyl-3-phenyl-4-(5-phenyl-2H-[1,2,4]triazol-3-yl)-pyrrol-1-yl]-3,5-dihydroxy-heptanoic    acid (Compound No. 10)

In Tables I and Ia, R₄ is the indicated structure, unless otherwisenoted.

TABLE I

C. No. R₁ R₂ R₃ R₄ R₅ R₆  1 4-Fluorophenyl Phenyl Isopropyl — Hydrogen2-Acetylphenyl  2 4-Fluorophenyl Phenyl Isopropyl — Hydrogen3-Acetylphenyl  3 4-Fluorophenyl Phenyl Isopropyl — Hydrogen4-Acetylphenyl  4 4-Fluorophenyl Phenyl Isopropyl — Hydrogen2,4-Dimethylphenyl  5 4-Fluorophenyl Phenyl Isopropyl — HydrogenCyclohexyl  6 4-Fluorophenyl Phenyl Isopropyl — Hydrogen4-trifluoromethyl benzyl  7 4-Fluorophenyl Phenyl Isopropyl ——(CH2)₂—O—(CH2)₂—  8 4-Fluorophenyl Phenyl Isopropyl — —(CH2)₅—  9*4-Fluorophenyl Phenyl Isopropyl 1,2,4-Oxadiazinylphenyl — 10*4-Fluorophenyl Phenyl Isopropyl 1,2,4-Triazolylphenyl — 114-Fluorophenyl Phenyl Isopropyl — Hydrogen 4-(Hydroxymethyl)phenyl 124-Fluorophenyl Phenyl Isopropyl — Hydrogen 4-(Methylsulfonamido)-phenyl13 4-Fluorophenyl Phenyl Isopropyl — Hydrogen 4-(Acetamido)phenyl 144-Fluorophenyl 4-cyanoPhenyl Isopropyl — Hydrogen Phenyl

*Hypothetical examples

TABLE Ia Formula I

Compound No. R₄    1a COOH    2a acetoxymethyl    3aphenylthiocarbamoyloxymethyl    4a propionyloxymethyl    5aoctylcarbamoyloxymethyl    6a phenylacetoxymethyl    7aphenylcarbamoyloxymethyl    8a benzoyloxymethyl    9aisonicotinoyloxymethyl   10a pyridin-4-ylcarbamoyloxymethyl   11aphenylcarbamoyl   12a cyclohexylcarbamoyl   13a methylcarbamoyl   14abenzylcarbamoyl 15 morpholine-4-carbonyl 16 piperidine-1-carbonyl 17benzylamino 18 (1-hydroxyethyl) 19 (2-hydroxyethyl) 20 (3-hydroxypropyl)21 methoxymethyl 22 ethoxymethyl 23 isopropoxymethyl 24 propoxymethyl 25methoxymethoxymethyl 26 cyclohexyloxymethyl 27 cyclopentyloxymethyl 28benzyloxymethyl 29 4-chlorobenzyloxymethyl 30 4-methoxybenzyloxymethyl31 phenoxymethyl 32 4-chlorophenoxymethyl 33 acetylamino 34 Benzoylamino36 benzenesulfonylamino 37 3-phenyl-ureido 38 3-methyl-ureido 393-benzyl-ureido 40 3-benzyl-thioureido 41 3-phenyl-thioureido 423-methyl-thioureido wherein

R₁ = 4-fluorophenyl, R₂ = phenyl, R₃ = isopropyl, R₅ = hydrogen

The term “pharmaceutically acceptable” means approved by regulatoryagency of the federal or a state government or listed in the U.S.Pharmacopeia or other generally recognized pharmacopeia for use inanimals, and more particularly in humans.

The term “pharmaceutically acceptable salts” refer to a salt preparedfrom pharmaceutically acceptable monovalent, divalent or trivalentnon-toxic metal or organic base. Examples of such metal salts include,but are not limited to, lithium, sodium, potassium, calcium, magnesium,zinc, aluminum, and the like. Examples of such organic bases include,but are not limited to, amino acid, ammonia, mono-alkyl ammonium,dialkyl ammonium, trialkyl ammonium and N-methyl glucamine and the like.The free acid forms of compounds of the present invention may beprepared from the salt forms, if desired, by contacting the salt withdilute aqueous solution of an acid such as hydrochloric acid. The baseaddition salts may differ from the free acid forms of the compounds ofthis invention in such physical characteristics as solubility andmelting point.

The term “pharmaceutically acceptable solvates” refers to solvates withwater (i-e hydrates) or pharmaceutically acceptable solvents, forexample solvates with ethanol and the like. Such solvates are alsoencompassed within the scope of the disclosure.

Furthermore, some of the crystalline forms for compounds describedherein may exist as polymorphs and as such are intended to be includedin the scope of the disclosure.

The present invention also includes within its scope prodrugs of theseagents. In general, such prodrugs will be functional derivatives ofthese compounds, which are readily convertible in vivo into the requiredcompound. Conventional procedure for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “design ofprodrugs”, ed. H Bundgaard and, Elsevier, 1985.

The present invention also includes metabolites, which become activeupon introduction into the biological system.

The compounds of the invention possess two chiral centers, they may,therefore, exist as enantiomers and diastereomers. It is to beunderstood that all such isomers and racemic mixtures therefore areencompassed within the scope of the present invention. Preferably, thisinvention contemplates compounds only with 3R and 5R configuration.

The crystalline or amorphous forms of compounds disclosed herein mayexist as polymorphs and as such are intended to be included in thepresent invention.

Pharmaceutical compositions comprising compounds disclosed herein, theirpharmaceutically acceptable salt, pharmaceutically acceptable solvates,or polymorphs, and pharmaceutically acceptable carrier or excipient arealso disclosed herein.

The compositions provided herein, both those containing one disclosedcompound and those containing two or more compounds, may be suitable fororal or parenteral administration. The compositions may be formulated toprovide immediate or sustained release of the therapeutic compounds. Thecompounds described herein can be administered alone but will generallybe administered as an admixture with a suitable pharmaceuticallyacceptable carrier. The term “pharmaceutically acceptable carrier” isintended to include non-toxic, inert solid, semi-solid, liquid filter,diluent, encapsulating materials or formulation auxiliaries of any type.

Solid form preparations for oral administration may include capsules,tablets, pills, powder, granules or suppositories. For solid formpreparations, the active compound is mixed with at least one inert,pharmaceutically acceptable excipient or carrier, for example, sodiumcitrate, dicalcium phosphate and/or a filler, an extender, for example,starch, lactose, sucrose, glucose, mannitol or silicic acid; binders,for example, carboxymethyl cellulose, alginates, gelatins,polyvinylpyrroledinone, sucrose, or acacia; disintegrating agents, forexample, agar-agar, calcium carbonate, potato starch, aliginic acid,certain silicates or sodium carbonate; absorption accelerators, forexample, quaternary ammonium compounds; wetting agents, for example,cetyl alcohol, glycerol, or mono stearate adsorbents, for example,Kaolin; lubricants, for example, talc, calcium stearate, magnesiumstearate, solid polyethyleneglycol, or sodium lauryl sulphate, andmixtures thereof.

In case of capsules, tablets, and pills, the dosage form may alsocomprise buffering agents.

The solid preparation of tablets, capsules, pills, or granules can beaccomplished with coatings and/or shells, for example, enteric coatingsand other coatings well known in the pharmaceutical formulating art.

Liquid form preparations for oral administration can includepharmaceutically acceptable emulsions, solutions, suspensions, syrupsand elixirs. For liquid form preparations, the active compound can bemixed with water or other solvent, solubilizing agents and emulsifiers,for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethyl formamide, oils (for example, cottonseed, ground corn,germ, live, caster and sesamine oil), glycerol and fatty acid ester ofsorbitan and mixture thereof.

Besides inert diluents, the oral compositions can also includeadjuvants, for example, wetting agents, emulsifying agents, suspendingagents, sweetening agents, flavoring agents and perfuming agents.

The formulations as described herein may be formulated so as to providequick, sustained, or delayed release of the active compound afteradministration to the patient by employing procedures well-known to theart. The term “patient” as used herein refers to a human or non-humanmammal, which is the object of treatment, observation or experiment.

The pharmaceutical preparations can be in unit dosage forms, and in suchforms, the preparations are subdivided into unit doses containingappropriate quantities of an active compound.

The amount of a compound disclosed herein that will be effective in thetreatment of a particular disorder or condition can be determined bystandard clinical techniques. In addition, in vitro or in vivo assaysmay optionally be employed to help identify optimal dosage ranges.

Examples set forth below demonstrate general synthetic procedures forpreparation of particular representative compounds. The examples areprovided to illustrate particular aspects of the disclosure, and do notconstrain the scope of the present invention as defined by the claims.

EXAMPLES General Procedure Schemes I and Ib Step 1: Preparation ofβ-ketoamide-1 (Formula IV and IVb)

A mixture of β ketoester (Formula II, 1 equiv.), amine (Formula III, 1equiv) 1,2-ethylenediamine (0.01 equiv) in xylene was refluxed with theazeotropic removal of water. After the completion of reaction, solventwas evaporated & the residue purified on column (silica gel; 100-200mesh). Compounds of Formula IVb can be prepared analogously. Thefollowing intermediates were prepared following above general procedure

4-Methyl-3-oxo-pentanoic acid (3-acetylphenyl)-amide

¹H NMR (CDCl₃): δ 1.19 (d, J=6.9 Hz, 6H), 2.61 (s, 3H), 2.75 (sep, J=6.9Hz, 1H), 3.64 (s, 2H), 7.43 (t, J=7.8 Hz, 1H), 7.71 (d, J=7.8 Hz, 1H),7.87 (d, J=8.1 Hz, 1H), 8.08 (s, 1H), 9.44 (brs, 1H); MS (positive ionmode): m/z 248 [M+1]; Yield: 49%

4-Methyl-3-oxo-pentanoic acid (4-acetylphenyl)-amide

¹H NMR (CDCl₃): δ 1.19 (d, J=6 Hz, 6H), 2.58 (s, 3H), 2.75 (sep, J=6 Hz,1H), 3.65 (s, 2H), 7.67 (d, J=6 Hz, 2H), 7.95 (d, J=6 Hz, 2H), 9.60 (s,1H), MS (positive ion mode): m/z 248 [M+1]; Yield 54%

4-Methyl-3-oxo-pentanoic acid (2,4-dimethylphenyl)-amide

¹H NMR (CDCl₃): δ 1.18 (d, J=6 Hz, 6H), 2.29 (s, 6H), 2.73 (Sep, J=6 Hz,1H), 3.64 (s, 2H), 7.00 (s, 2H), 7.76 (d, J=6 Hz, 1H), 9.11 (brs, 1H);MS (positive ion mode): m/z 234 [M+1] Yield 72%

4-Methyl-3-oxo-pentanoic acid 4-trifluoromethylbenzyl amide

¹H NMR (CDCl₃): δ 1.14 (d, J=6 Hz, 6H), 2.70 (sept, J=6 Hz, 1H), 3.53(s, 2H), 4.53 (d, J=6 Hz, 2H), 7.40 (d, f=6 Hz, 2H), 7.59 (d, J=6 Hz,2H); MS (positive ion mode): m/z 287

4-Methyl-1-piperidin-1-yl-pentane-1,3-dione

¹H NMR (CDCl₃, 300 MHz): δ 1.14 (d, J=6 Hz, 6H), 1.57-1.65 (m, 6H), 2.76(brs, 1H), 3.20-3.75 (m, 6H);

4-Methyl-3-oxo-pentanoic acid phenylamide Step 2: Preparation of(3-ketoamide-2 (Formula VI and VIb)

To β-ketoamide-1 (Formula IV, 1 equiv) in hexane was added to β-alanine(0.18 equiv), aldehyde (Formula V, 1.1 equiv) and glacial acetic acid(0.16% w/w of β-ketoamide-1). The resulting suspension was heated underreflux with the azeotropic removal of water. The reaction mixture wascooled and product was isolated by filtration. The product was purifiedby washing the precipitate with hot hexane, water and dried in vacuo toafford β-ketoamide-2. Compounds of Formula VIb can be preparedanalogously. The following intermediates were prepared following abovegeneral procedure

2-Benzylidine-4-methyl-3-oxo-pentanoic acid (3-acetylphenyl)-amide;Isomer-1

¹H NMR (CDCl₃): δ 1.1 (d, J=6.9 Hz, 6H), 2.50-2.70 (m, 4H), 7.28-7.52(m, 6H), 7.73 (d, J=7.2 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 8.19 (d, J=9.9Hz, 2H), 9.23 (s, 1H); MS (positive ion mode): m/z 336 [M+1]; Yield: 13%

2-Benzylidine-4-methyl-3-oxo-pentanoic acid (3-acetylphenyl)-amide;Isomer-2

¹H NMR (CDCl₃): δ 1.24 (d, J=9 Hz, 6H), 2.60 (s, 3H), 3.39 (sep, J=6 Hz,1H), 7.33-7.98 (m, 11H); MS (positive ion mode): m/z 336 [M+1]; Yield:32%

2-Benzylidene-4-methyl-3-oxo-pentanoic acid (4-acetylphenyl)-amide

¹H NMR (CDCl₃): δ 1.23 (d, J=6.6 Hz, 6H), 2.58 (s, 3H), 3.37 (Sep, J=6.6Hz, 1H), 7.27-7.42 (m, 3H), 7.49-7.73 (m, 5H), 7.95 (d, f=8.7 Hz, 2H);MS (positive ion mode): ink 336 [M+1]

Yield 48%

2-Benzylidene-4-methyl-3-oxo-pentanoic acid (2,4-dimethylphenyl)-amide

¹H NMR (CDCl₃): δ 1.23 (d, J=6 Hz, 6H), 1.99 (s, 1H), 2.29 (s, 1H), 3.38(Sep, J=6 Hz, 1H), 6.97 (s, 1H), 7.04 (d, J=6 Hz, 1H), 7.30 (s, 1H),7.35-7.45 (m, 3H), 7.53-7.72 (m, 7H)

MS (positive ion mode): m/z 323 [M+1]; Yield 50%

2-Benzylidine-4-methyl-3-oxo-pentanoic acid 4-trifluoromethylbenzylamide

¹H NMR (CDCl₃,300 MHz): δ 1.19 (d, J=6.9 Hz, 6H), 3.30 (sept, J=6.9 Hz,1H), 6.16 (brs, 1H), 7.26-7.60 (m, 10H)

2-Benzylidene-4-methyl-1-piperidin-1-yl-pentane-1,3-dione

¹H NMR (CDCl₃, 300 MHz): δ 0.88-0.97 (m, 2H), 1.15-1.35 (m, 8H),1.43-1.62 (m, 4H), 3.13-3.30 (m, 3H), 3.61 (brs, 1H), 3.78 (brs, 1H),7.38 (brs, 3H), 7.54 (brs, 3H); MS (positive ion mode): m/z 286 (M⁺+1)

2-(4-Cyanobenzylidene)-4-methyl-3-oxo-pentanoic acid phenylamide

¹H NMR (CDCl₃): δ 1.23 (d, J=6 Hz, 6H), 3.34 (Sep, J=6 Hz, 1H), 7.18 (t,J=6 Hz, 1H), 7.36 (t, J=6 Hz, 2H), 7.48 (d, J=6 Hz, 2H), 7.57 (s, 1H),7.65 (s, 4H), 7.81 (s, 11-1); MS (positive ion mode): m/z 319 [M+1];Yield: 67%

Step 3: Preparation of Diketone (Formula VIII and VIIIb)

β-ketoamide-2 (Formula VI, 1 equiv), aldehyde (Formula VII, 1.1 equiv),triethylamine (1 equiv) ethanol and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (0.2 equiv) were placed in a vial. The contents wereflushed with N₂ and the vial was capped immediately and was heated to78° C. After the completion of reaction, contents were cooled andtriturated with ethyl acetate. The organic layer was washed with 6Nhydrochloric acid, water, dried over anhydrous sodium sulphate,concentrated on rotary evaporator and residue was purified on achromatographic column (silica gel, 100-200 mesh). Compounds of FormulaVIIIb can be prepared analogously. The following intermediates wereprepared following above general procedure

2-[2-(Fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoic acid(3-acetylphenyl)-amide

¹H NMR (CDCl₃): δ 1.15 (d, J=6 Hz, 3H), 1.20 (d, J=6 Hz, 3H), 2.58 (s,3H), 2.99 (sep, J=6 Hz, 1H), 4.61 (d, J=12 Hz, 1H), 5.38 (d, J=12 Hz,1H), 7.05 (t, I=9 Hz, 2H), 7.15-7.44 (m, 6H), 7.54-7.72 (m, 4H),7.94-8.05 (m, 2H); MS (positive ion mode): m/z 460 [M+1]; Yield: 55%

2-[2-(4-Fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid(4-acetylphenyl)-amide

¹H NMR (CDCl₃): δ 1.16 d, J=6.9 Hz, 3H), 1.23 (d, J=6.9 Hz, 3H), 2.55(s, 3H), 2.99 (Sep, J=6.6 Hz, 1H), 4.56 (d, J=10.5 Hz, 1H), 5.35 (d,J=10.8 Hz, 1H), 7.04 (t, J=8.7 Hz, 3H), 7.18-7.37 (brm, 6H), 7.48 (s,1H), 7.86 (d, J=8.4 Hz, 2H), 7.87-8.03 (m, 2H); MS (positive ion mode):m/z 460 [M+1]; Yield 64%

2-[2-(4-Fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-pentanoic acid(2,4-dimethylphenyl)-amide

¹H NMR (DMSO-d₆): δ 0.99 (d, J=6.6 Hz, 3H), 1.19 (d, J=6.9 Hz, 3H), 1.67(s, 3H), 2.18 (s, 3H), 3.00 (Sep, 1=6.9 Hz, 1H), 4.94 (d, J=11.1 Hz,1H), 5.36 (d, s=10.8 Hz, 1H), 6.68 (d, J=8.1 Hz, 1H), 6.82-6.93 (m, 2H),7.17-7.45 (m, 7H), 8.08-8.24 (m, 2H), 9.60 (brs, 1H) MS (positive ionmode): m/z 446 [M+1]; Yield 66%

2-[2-(4-Fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoicacid 4-trifluoromethylbenzyl amide

¹H NMR (CDCl₃, 300 MHz): δ 1.10 (d, J=6.6 Hz, 3H), 1.16 (d, J=7.2 Hz,3H), 2.88 (sept, J=6.9 Hz, 1H0, 4.15 (dd, J=15 & 4.8 Hz, 1H), 4.40 (dd,J=15.9 & 6.6 Hz, 1H), 4.46 (d, J=11.1 Hz, 1H), 5.32 (d, J=10.8 Hz, 1H),5.80 (brs, 1H), 6.89 (d, J=7.8 Hz, 2H), 6.97 (t, J=8.4 Hz, H), 7.45 (d,J=7.5 Hz, 2H), 7.94-7.98 (m, 2H); MS (positive ion mode): m/z 500 (M⁺+1}

1-(4-Fluorophenyl)-5-methyl-2-pentyl-3-(piperidine-1-carbonyl-hexane-1,4-dione

¹H NMR (CDCl₃, 300 MHz): δ 1.05 (d, J=6.9 Hz, 3H), 1.19 (d, J=7.1 Hz,411), 1.45 (brs, 5H), 2.62 (sept, J=6.8 Hz, 1H), 2.95-3.15 (m, 1H),3.20-3.40 (m, 2H), 3.45-3.60 (m, 1H), 4.99 (d, J=10.5 Hz, 1H), 5.34 (d,J=10.6 Hz, 1H), 7.03 (t, J=8.5 Hz, 2H), 7.24 (brs, 5H), 7.97-8.07 (m,2H); MS (positive ion mode): m/z 493 (M⁺+1)

2-[1-(4-Cyanophenyl)-2-(4-fluorophenyl)-2-oxo-ethyl]-4-methyl-3-oxo-pentanoicacid phenylamide

MS (positive ion mode): m/z 443 [M+1]

Step 4: Preparation of Pyrrole (Formula X and Xb)

A mixture of diketone (Formula VIII, 1 equiv), amine (Formula IX, 1.00,equiv) and pivalic acid (1.03 equiv) in heptane:toluene:tetrahydrofuran(4:1:1) was refluxed and water was removed using Dean Stark trap. Afterthe completion of reaction, solvents were removed and the residue wasdissolved in ethyl acetate. The organic layer was washed in saturatedsodium bicarbonate, water, dried over anhydrous sodium sulphate,concentrated on rotary evaporator and the residue was purified on achromatographic column (silica gel, 100-200 mesh). Compounds of FormulaXb can be prepared analogously. The following intermediates wereprepared following above general procedure

(6-{2-[3-(3-Acetylphenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-aceticacid tert-butyl ester

¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.36 (s, 3H), 1.43 (s, 9H), 1.53 (d, J=6Hz, 6H), 1.67 (brs, 2H), 2.20-2.43 (m, 2H), 2.52 (s, 3H), 3.52-3.75 (m,2H), 3.76-3.88 (m, 1H), 4.00-4.22 (m, 2H), 6.85-7.05 (m, 3H), 7.10-7.51(m, 10H), 7.58 (d, J=9 Hz, 1H); MS (positive ion mode): m/z 697 [M+1];Yield: 23%

(6-{2-[3-(4-Acetylphenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-aceticacid tert-butyl ester

¹H NMR (CDCl₃): δ 1.31 (s, 3H), 1.38 (s, 3H), 1.44 (s, 9H), 1.53 (d, J=9Hz, 6H), 1.66 (brs, 2H), 2.22-2.49 (m, 2H), 2.54 (s, 3H), 3.49-3.75 (m,2H), 4.00-4.25 (m, 2H), 7.01 (t, J=6 Hz, 2H), 7.06-7.26 (m, 10H), 7.81(d, J=9 Hz, zH); MS (positive ion mode): m/z 698 [M+1]; Yield: 14%

(6-{2-[3-(2,4-Dimethylphenylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-aceticacid tert-butyl ester

¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.36 (s, 3H), 1.43 (s, 9H), 1.52 (d, s=6Hz, 6H), 1.65-1.76 (m, 2H), 118-2.32 (m, 4H), 2.33-2.47 (m, 1H), 3.48(Sep, J=6 Hz, 1H), 3.63-3.90 (m, 2H), 4.0-4.25 m, 2H), 6.72 (s, 1H),6.81 (s, 1H), 6.99 (t, S=6 Hz, 3H), 7.07-7.25 (m, 711), 7.88 (d, J=6 Hz,1H); MS (positive ion mode): m/z 684 [M+1]; Yield 21%

(6-{2-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(4-trifluoromethylbenzylcarbamoyl)-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)aceticacid tert-butyl ester

¹H NMR (CDCl₃, 300 MHz): δ 0.8-1.2 (m, 2H), 1.29 (s, 3H), 1.35 (s, 3H),1.43 (s, 9H), 1.63 (brs, 2H), 2.22-2.27 (m, 1H), 2.38 (dd, J=15.0 & 6.0Hz, 1H), 9.36-3.50 (m, 1H), 3.6-3.7 (m, 1H), 3.71-3.85 (m, 1H), 4.1-4.25(m, 2H), 4.38 (d, J=6.0 Hz, 2H), 7.02-7.16 (m, 12H), 7.41 (d, J=9.0 Hz,2H); MS (positive ion): ink 737.4 [M+1]⁺

6-{2-[2-(4-Fluorophenyl)-5-isopropyl-3-phenyl-4-(piperidine-1-carbonyl)-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-aceticacid tert-butyl ester

¹H NMR (CDCl₃, 300 MHz): δ 0.99-1.60 (m, 29H), 2.17-2.52 (m, 2H),2.80-3.25 m, 3H), 3.35-3.50 (m, 1H), 3.65-3.90 (m, 3H), 3.90-4.25 (m,3H), 6.91-7.19 (m, 9H); MS (positive ion mode): m/z 646 (M⁺+1)

(6-{2-[3-(4-cyanophenyl)-5-isopropyl-2-(4-fluorophenyl)-4-(phenylamino)carbonyl-pyrrol-1-yl]ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)acetic acidtert-butyl ester

¹H NMR (CDCl₃): δ 1.30 (s, 3H), 1.36 (s, 3H), 1.44 (s, 9H), 1.50 (d,J=6.9 Hz, 6H), 1.67 (brs, 3H), 1.55-1.75 (brm, 3H), 2.20-2.40 (m, 2H),3.38 (sep, J=6.6 Hz, 1H), 3.63-3.88 (m, 2H), 3.97-4.24 (m, 2H), 6.85 (s,1H), 6.96-7.48 (m, 12H); MS (positive ion mode): m/z 680 [M+1]; Yield:20%

Step 5: Preparation of hemi calcium salt of compound of Formula XI andXIb

(a) To a solution of a compound of Formula X in methanol andtetrahydrofuran (1:1) was added 1N hydrochloric acid (3 equiv) and themixture was stirred at ambient temperature. After the completehydrolysis of the ketal, the reaction mixture was cooled to 0° C. andsodium hydroxide pellets (6 equiv) were added. The reaction was thenstirred at ambient temperature. At the end of ester hydrolysis, solventswere removed and the residue was dissolved in water; aqueous layer waswashed with ether, and was neutralized with 1N hydrochloric acid. Theorganic phase was extracted into ethyl acetate, and concentrated. Theresidue was then purified on a chromatographic column (silica gel100-200 mesh).

(b) To an aqueous solution of sodium salt of acid (is prepared by adding1 equivalent 1N sodium hydroxide solution) was added dropwise an aqueoussolution (1M) of calcium acetate (0.55 equiv). White precipitate wasobtained, which was filtered off, washed with copious amount of water,and dried in vacuo.

Compounds of Formula XIb and XIIb can be formed analogously. Thefollowing compounds were prepared following above general procedure

Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(3-acetylphenylamino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid

¹H NMR (DMSO-d₆): δ 1.23 (brs, 2H), 1.38 (d, J=6 Hz, 6H), 1.63 (brs,2H), 1.90-2.15 (m, 2H), 3.52 (brs, 1H), 3.76 (brs, 2H), 3.99 (brs, 1H),6.95-7.45 (m, 1011), 7.60 (d, J=7.5 Hz, 1H), 7.71 (d, J=7.5 Hz, 1H),8.15 (s, 1H), 9.98 (s, 1H, D₂O exchanged); MS (positive ion mode): m/z601 [Acid+1]; Yield: 21.35; m.pt: 167.5-204° C.

Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylphenylamino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid

¹H NMR (DMSO-d₆): δ 1.24 (brs, 2H), 1.37 (d, J=6 Hz, 6H), 1.58 (brs,2H), 1.88-1.99 (m, 1H), 2.00-2.12 (m, 1H), 3.53 (brs, 1H), 3.73 (brs,2H), 3.96 (brs, 1H), 7.09 (brs, 5H), 7.14-7.37 (m, 4H), 7.66 (d, J=9 Hz,2H), 7.85 (d, J=9 Hz, 2H), 10.21 (s, 1H, D₂O exchanged); MS (positiveion mode): m/z 601 [Acid+1]; Yield 23%; m.pt 188.9-216.5° C.

Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(2,4-dimethylphenylamino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid

¹H NMR (DMSO): δ 1.29 (brs, 2H), 1.31-1.76 (m, 11H), 1.87-2.01 (dd, J=15& 6 Hz, 1H), 2.02-2.15 (dd, 3=15 & 3 Hz, 1H), 2.19 (s, 3H), 3.59 (brs,1H), 3.76 (brs, 2H), 3.95 (brs, 1H), 6.85-6.95 (m, 2H), 7.05-7.33 (m,10H), 8.78 (s, 1H, D₂O exchanged); MS (positive ion mode): m/z 587[Acid+1]; Yield 45%; m.p 172.6-198.9° C.

Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-trifluoromethylbenzylamino)carbonyl)]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid

¹H NMR (DMSO-d₆,300 MHz): δ 1.15-1.24 (m, 2H), 1.31 (d, J=6 Hz, 6H),1.48-1.56 (m, 2H), 1.84 (dd, J=158, 7.8 Hz, 1H), 2.01 (dd, J=15 &4.2 Hz,1H), 3.15-3.33 (m, 1H), 3.42 (brs, 1H), 3.50 (brs, 1H), 3.68-3.73 (m,2H), 3.80-4.02 (m, 1H), 4.29 d, J=5.4 Hz, 1H), 6.99 (brs, 2H), 7.05(brs, 3H), 7.12-7.23 (m, 6H), 7.50 (d, J=8.1 Hz, 2H), 8.24 (t, J=5.4 Hz,1H); MS (positive ion mode): m/z 641 (acid+1)

Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-(piperidine-1-carbonyl)-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid

¹H NMR (DMSO-d₆, 300 MHz, D₂O exchanged): δ 1.08-1.13 (m, 2H), 1.24(brs, 7H), 1.27 (d, J=9 Hz, 6H), 1.43 (brs, 2H), 2.02 (dd, J=15 & 6 Hz,1H), 2.15-2.19 (m, 1H), 2.88-2.95 (m, 2H), 3.12-3.24 m, 2H), 3.64-3.69(m, 3H), 6.95 (d, J=6 Hz, 2H), 7.05-7.15 (m, 5H), 7.25 (brs, 2H), 8.08(s, 1H).

Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-(4-cyanophenyl)-4-[(phenylamino)carbonyl)]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid

¹H NMR (DMSO-d₆): δ 1.24 (brs, 2H), 1.37 (d, J=6 Hz, 6H), 1.45-1.73 (m,2H), 1.87-2.15 (m, 2H), 3.10-3.60 (m, 2H), 3.70-3.90 (brm, 2H),3.91-4.08 (brm, 1H), 7.01 (t, J=6 Hz, 1H), 7.13-7.35 (m, 8H), 7.45-7.63(m, 4H), 10.02 (s, 1H, D₂O exchanged); MS (positive ion mode): m/z 584[Acid+1]; Yield: 87%; m.pt. 197.7-222.1° C.

Scheme Ia Step 1: Preparation of Compound of Formula XIV

Compound XIII (prepared following the appropriate steps of Scheme Itoproduce a compound of Formula X with appropriate substitution) wasdissolved in tetrahydrofuran:methanol (1:2) mixture and 1N lithiumhydroxide (equiv) was added. The reaction mixture was stirred at 0° C.for 12 to 15 hours. After completion of reaction, reaction mixture wasacidified and the solvent was evaporated under reduced pressure to getcrude product. The crude product was purified by column chromatography(silica gel—100-200 mesh) using 50% ethyl acetate in hexane. Thefollowing intermediates wee prepared in this fashion.

4-{[1-[2-(6-tert-butoxycarbonylmethyl-2,2-dimethyl-[1,3]dioxan-4-yl)-ethyl]-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-3-carbonyl]-amino}-benzoicacid

¹H NMR (CDCl₃): δ 1.03-1.11 (m, 1H), 1.26 (s, 3H), 1.30 (s, 3H), 1.43(s, 9H), 1.53 (d, J=7.2 Hz, 3H), 1.65-1.69 (m, 2H), 2.23 (dd, J=15.6 &6.3 Hz, 1H), 2.40 (dd, J=15.6 & 6.3 Hz, 1H), 3.63-3.71 (m, 2H), 3.75-3.8(m, 1H), 4.05-4.20 (m, 2H), 6.96-7.20 (m, 12H), 7.90 (d, J=8.4 Hz, 2H);MS (positive ion mode): m/z 698 (M⁺+1); Yield=51%

Step 2: Preparation of Compound of Formula XV

Method A: Compound XIV (1 equiv) was dissolved in dry tetrahydrofuranand sodium borohydride (2 equiv) was added slowly in two to threefractions. The resulting suspension was stirred for 5 minutes at 0° C. Asolution of iodine (1 equiv) in tetrahydrofuran was added slowly at 0°C. and reaction mixture was stirred for 24 to 30 hours at an ambienttemperature. At the end of reaction, solvent was evaporated to get crudeproduct. The crude product was purified by column chromatography (silicagel, 100-200 mesh) using 25% ethyl acetate in hexane.

¹H NMR (CDCl₃, 300 MHz): δ 1.02=1.06 (m, 1H), 1.26 (s, 3H), 1.33 (s,3H), 1.43 (s, 9H), 1.55 (d, J=6 Hz, 6H), 2.21 (dd, J=15 & 6 Hz, 1H),2.38 (dd, J=15 & 6 Hz, 1H), 2.40-4.17 (m, 5H), 4.58 (s, 2H), 6.87-7.19(m, 13H); MS (+ve ion mode): m/z 685 (M⁺+1); Yield=87%

Method B: A mixture of compound of Formula XIV (1 equiv.) andtetrahydrofuran (4 mL, Dry) was placed in a 3 neck round bottom flaskequipped with a reflux condenser, nitrogen was purged. The reactionmixture was heated at about 50° C. and borane dimethylsulphide (2equiv.) was added dropwise over 1 hour. Water (6 mL) was added to thereaction mixture, solvent was evaporated. Solid residue was dissolved inethyl acetate, washed with water and the aqueous layer was extractedwith ethyl acetate. The organic layer was washed with brine, dried overanhydrous sodium sulphate, concentrated. The crude product was purifiedby silica gel column chromatography using ethyl acetate and hexane aseluant.

Yield: 2.16 g (73.72%)

Step 3: Preparation of Hemi Calcium Salt of Formula XVI

(a) To a solution of XV in methanol and tetrahydrofuran (1:1) was added1N hydrochloric acid (3 equiv) and the mixture stirred at an ambienttemperature. After the complete hydrolysis of ketal, the reactionmixture was cooled to 0° C. and sodium hydroxide pellets (6 equiv) wereadded. The reaction was then allowed to stir at ambient temperature. Atthe end of ester hydrolysis, solvents were removed and the residue wasdissolved in water; the aqueous layer was washed with ether, andneutralized with 1N hydrochldric acid. The organic phase was extractedinto ethyl acetate, and concentrated. The residue was then purified oncolumn (silica gel 100-200 mesh).

(b) To an aqueous solution of the sodium salt of the acid (prepared byadding 1 equivalent 1N sodium hydroxide solution) was added dropwise anaqueous solution (1M) of calcium acetate (0.55 equiv). White precipitatewas obtained, which was filtered off and washed with copious amount ofwater, and dried in vacuo.

The following compound was prepared similarly.

Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-hydroxymethylphenylamino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoicacid

¹H NMR (DMSO-d₆): δ 1.22-1.62 (M, 11H), 1.98 (dd, J=15 & 8.1 Hz, 1H),2.06-2.16 (m, 1H), 3.25-3.37 (m, 2H), 3.57 (brs, 2H), 3.80 (brs, 1H),4.43 (s, 2H), 7.03-7.28 (m, 12H), 7.50 (d, J=6H, 2H), 9.80 (s, 1H); MS(positive ion mode): m/z 589 (Acid+1); Yield=−31%; m.p. 189-204° C.

Scheme IIa Step 1: Preparation of Compound of Formula XVa

A compound of Formula XIIIa (1 equiv.) and a mixture of 1N hydrochloricacid:methanol:tetrahydrofuran (2:5:5) were stirred at room temperaturefor about 7 hours. At the end of reaction, sodium hydroxide pellets (7equiv.) were added and the reaction mixture was further stirred at roomtemperature for about 5 hours. Reaction mixture was concentrated and theresidue was dissolved in distilled water and acidified to ˜1 pH with 1Nhydrochloric acid. The aqueous layer was extracted with ethyl acetate,washed with water, brine and dried over anhydrous sodium sulphate.Organic layer was concentrated and adsorbed over silica gel (5%methanol-dichloromethane). The following compound was prepared byfollowing above procedures

(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-carboxyphenyl)amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid

Yield: 5 g (84.6%)

Step II: Preparation of Disodium Salt of Compound of Formula XVa

A compound of XVa (1 equiv.), tetrahydrofuran:methanol (1:1) and sodiumhydroxide (1N, 2 equiv.) solution were stirred at ambient temperaturefor about 2 hours. Disodium salt of compound of Formula XVa was isolatedby evaporating solvent under reduced pressure. The residue was washedwith diethylether, dried in vacuo to afford the pure compound in a yieldof 4.5 g (84.9%). The following compound was prepared by following aboveprocedures.

Disodium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-carboxyphenyl)amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid

¹H NMR (DMSO, 300 MHz): δ 1.135-1.179 (m, 2H), 1.365 (d, J=6.3 Hz, 6H),1.752 (brs, 4H), 1.752-1.779 (m, 1H), 1.950-1.998 (m, 1H), 2.733 (s,1H), 2.89 (s, 1H), 3.607-3.75 (m, 3H), 3.924-4.004 (m, 2H), 6.99-7.07(m, 5H), 7.155-7.247 (m, 4H), 7.4 (d, J=6 Hz, 2H), 7.70 (d, J=9 Hz, 2H),9.827 (s, 1H); MS (positive ion mode): m/z 603.13 (Acid⁺+1); Yield: 4.5g (84.9%).

Scheme II Preparation of Compound of Formula XIX

To a solution of a compound of Formula XVIII (4.5 mmoles; preparedaccording to procedure as described in Tet. Let., 43:1161 (2002) and J.Org. Chem., 50:438 (1985), in toluene (15 ml) was added a compound ofFormula V (4.9 mmoles), piperidine (0.02 ml) and acetic acid (0.054 ml).The mixture was heated at reflux with azeotropic removal of water forabout 4 to 6 hours. The reaction mixture was concentrated and theresidue was extracted in dichloromethane. The organic layer was washedwith 1N hydrochloric acid solution, sodium bicarbonate solution, brine,dried over anhydrous sodium sulphate, and concentrated. The crudeproduct was purified on a chromatographic column (silica gel, 100-200mesh, 2% EtOAc-hexane).

Preparation of Compound of Formula XX

A compound of Formula XIX (6.49 mmoles), a compound of Formula VII (7.14mmoles), 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide (1.298mmoles), triethylamine (6.49 mmoles), and ethanol (0.6 ml) were placedin a 30 ml vial, flushed with argon and the vial sealed properly. Thereaction mixture was stirred at 70° C. for about 12 to 15 hours. To thereaction mixture was added ethyl acetate, the mixture was washed withwater, 6N hydrochloric acid, again with water and brine, dried overanhydrous sodium sulphate, and concentrated to give crude product. Thecrude product was purified on a chromatographic column (silica gel100-200 mesh) using 7% ethyl acetate in hexane.

Preparation of Compound of Formula XXI

To a solution of Formula XX (4.62 mmoles) in heptane:toluene:tetrahydrofuran (4:1:1) was added a compound of Formula IX (6.99mmoles) and pivalic acid (4.768 mmoles). The mixture was refluxed withazeotropic removal of water for about 22 to 25 hours. The reactionmixture was concentrated, ethyl acetate was added, the reaction mixturewas washed with sodium bicarbonate solution and brine, dried overanhydrous sodium sulphate and concentrated to give the crude product.The crude product was purified on column (silica gel, 100-200 mesh)using 7% ethyl acetate in hexane.

Preparation of Compound of Formula XXII

To a solution of a compound of Formula XXI (0.8 g) in methanol:dioxan(2:8) mixture was added 10% palladium carbon (50% wet, 60% w/w). Theresulting reaction mixture was hydrogenated at 40 psi for about 2.5hours. After the reaction was over, the reaction mixture was passedthrough celite and the resulting solution was concentrated under vacuumto give the required product, which was further used as such for nextstep.

Preparation of Compound of Formula X: Path a

To a solution of a compound of Formula XXII (1 equiv) in benzene at 0°C. under argon, oxalyl chloride (2.0 equiv) was added dropwise. Afterthe evolution of gas had ceased, the reaction mixture was heated on oilbath at 70° C. for 2 hours. The reaction mixture was evaporated todryness. The residue was dissolved in benzene (dry) and added at ambienttemperature to a solution of amine of formula III (1.1 equiv.) inbenzene. The reaction mixture was then heated to 70° C. until completionof reaction. Volatiles were removed in vacuo and the residue waspurified on a chromatographic column (silica gel, 100-200 mesh). Thefollowing compound was prepared following above general procedure

(6-{2-[3-(2-Acetylphenylearbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-aceticacid tert-butyl ester

¹H NMR (CDCl₃, 300 MHz): δ 1.0-1.15 (m, 1H), 1.30 (s, 1H), 1.33 (s, 3H),1.44 (s, 9H), 1.48 (d, J=6.0 Hz, 6H), 2.23 (dd, J=15.0 & 6.0 Hz, 1H),2.35-2.5 (m, 4H), 3.35 (sept. J=6.0 Hz, 1H), 3.64-3.89 (m, 2H), 4.0-4.25(m, 2H), 6.93-7.08 (m, 8H), 7.18-7.22 (m, 2H), 7.50 (d, J=9.0 Hz, 1H),7.69 (d, J=6.0 Hz, 1H), 8.82 (d, J=9.0 Hz, 1H), 11.02 (brs, 1H); MS(positive ion): m/z 697.500 [M+1]⁺; Yield=59%

Preparation of Compound of Formula X: Path b

To a solution of a compound of Formula XXII (1.2 mmole) indimethylformamide (2.5 ml) was added diisopropylethylamine (2.4 mmole)and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl uroniumhexafluorophosphate (HBTU) (1.2 mmoles). To the resulting clear solutionwas then added cyclohexylamine (1.2 mmoles) in dimethylformamide (0.5ml). The reaction mixture was stirred at 50° C. to 60° C. overnight. Tothe reaction mixture was added water and the mixture was extracted withdichloromethane, the organic layer was washed with water, brine, driedover anhydrous sodium sulphate and concentrated to get the crudeproduct. The crude product was purified by column chromatography (silicagel, 100-200 mesh) using 10% ethyl acetate in hexane. The followingcompound was prepared as per this protocol.

(6-{2-[3-Cyclohexylcarbamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-pyrrol-1-yl]-ethyl}-2,2-dimethyl-[1,3]dioxan-4-yl)-aceticacid tert-butyl ester

¹H NMR (CDCl₃, 300 MHz): δ 0.7-0.88 (m, 2H), 0.97-1.05 (m, 2H),1.20-1.30 (m, 4H), 1.30-1.34 (s, 3H), 1.43 (s, 9H), 1.47 (d, f=6.9 Hz,6H), 1.43-1.48 (m, 2H), 1.63 (brs, 31-1), 2.25 (dd, J=15 & 6 Hz, 1H),2.35 (dd, J=15 & 6.9 Hz, 1H), 3.35 (sept, J=6.9 Hz, 1H), 3.69-3.81 (m,3H), 3.85-4.15 (m, 1H), 4.15-4.25 (m, 1H), 6.91-6.99 (m, 3H), 7.07-7.15(m, 6H); MS (positive ion mode): m/z 661 (M⁺+1)

Preparation of Hemi Calcium Salt of Formula XI

(a) To a solution of a compound of Formula X in methanol andtetrahydrofuran (1:1) was added 1N hydrochloric acid (3 equiv) and themixture stirred at ambient temperature. After the complete hydrolysis ofketal, the reaction mixture was cooled to 0° C. and sodium hydroxidepellets (6 equiv) were added. The reaction was then stirred at ambienttemperature. At the end of ester hydrolysis, solvents were removed andthe residue was dissolved in water; the aqueous layer was washed withether, and neutralized with 1N hydrochloric acid. The organic phase wasextracted into ethyl acetate, and concentrated. The residue was thenpurified on a chromatographic column (silica gel 100-200 mesh).

(b) To an aqueous solution of the sodium salt of the acid (prepared byadding 1 equivalent 1N sodium hydroxide solution) was added dropwise anaqueous solution (1M) of calcium acetate (0.55 equiv). White precipitatewas obtained, which was filtered, washed with copious amount of water,and dried in vacuo.

The following compounds were prepared following above general procedure

Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(cyclohexylamino)carbonyl)]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid

¹H NMR (DMSO-d₆, D₂O exchanged, 300 MHz): δ 0.99 (brs, 2H), 1.2-1.35 (m,5H), 1.35-1.50 (m, 7H), 1.55 (m, 4H), 1.90-2.1 (m, 1H), 2.10-2.20 (m,1H), 3.17-3.20 (m, 1H), 3.51 (brs, 1H), 3.73 (brs, 1H), 7.02-7.36 (m,91-1); MS (positive ion mode): m/z 565 (acid+1).

Hemi calcium salt of(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(2-acetylphenylamino)carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid

¹H NMR (DMSO-d₆,300 MHz): δ 1.10-1.25 (m, 2H), 139 (d, J=6.0 Hz, 6H),1.5-1.7 (m, 2H), 1.77 (dd, J=150 & 6.0 Hz, 1H), 1.97 (dd, J=15.0 & 3.0Hz, 1H), 2.38 (s, 3H), 6.94-7.01 (m, 5H), 7.08-7.20 (m, 3H), 7.29-7.34(m, 2H), 7.56 (t, J=9.0 Hz, 1H), 7.87 (d, J=6.0 Hz, 1H), 8.58 (d, 9.0Hz, 1H), 10.98 (s, 1H); MS (positive ion): m/z 601.300 [Acid+1]⁺;Yield=28%; m. pt: 202.6-208.7° C.

Scheme IIIa Preparation of Compound of Formula XIX

To a solution of a compound of Formula XVIII (4.5 mmoles; preparedaccording to procedure as described in Tet. Let., 43:1161 (2002) and J.Org. Chem., 50:438 (1985)) in toluene (15 ml) was added a compound ofFormula V (4.9 mmoles), piperidine (0.02 ml) and acetic acid (0.054 ml).The mixture was heated at reflux with azeotropic removal of water forabout 4 to 6 hours. The reaction mixture was concentrated and theresidue was extracted in dichloromethane. The organic layer was washedwith 1N hydrochloric acid solution, sodium bicarbonate solution, brine,dried over anhydrous sodium sulphate, and was concentrated. The crudeproduct was purified on a chromatographic column (silica gel, 100-200mesh, 2% EtOAc-hexane).

¹H NMR (CDCl₃, 300 MHz): δ 1.02 (d, J=6.9 Hz, 6H), 2.65 (sept, J=7.2 Hz,1H), 5.26 (s, 2H), 7.25 (s, 2H), 7.25 (brs, 10H), 7.81 (s, 1H).). isomer2: ¹H NMR (CDCl₃, 300 MHz): δ 1.02 (d, J=6.9 Hz, 6H), 2.65 (sept, J=6.9Hz, 1H), 5.27 (s, 2H), 7.36 (brs, 10H), 7.82 (s, 1H) MS (+ve ion mode):ink 309 (M⁺+1); Yield: 70%

Preparation of Compound of Formula XX

A compound of Formula XIX (6.49 mmoles), a compound of Formula VII (7.14mmoles), 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide (1.298mmoles), triethylamine (6.49 mmoles), and ethanol (0.6 ml) were placedin a 30 ml vial, the reaction was flushed with argon and the vial wassealed properly. The reaction mixture was stirred at 70° C. for about 12to 15 hours. To the reaction mixture was added ethyl acetate, themixture was washed with water, 6N hydrochloric acid, again with waterand brine, was dried over anhydrous sodium sulphate, and wasconcentrated to give crude product. The crude product was purified on achromatographic column (silica gel 100-200 mesh) using 7% ethyl acetatein hexane.

¹H NMR (CDCl₃, 300 MHz): (1:1 mixture of diastereomers) δ 0.48 (d, J=6.9Hz, 3H), 0.91 (d, J=6.6 Hz, 3H), 1.07 (d, J=−6.6 Hz, 3H), 1.21 (d, J=6.9Hz, 3H), 2.30 (sept, J=6.6 Hz, 1H), 2.82 (sept, 6.6 Hz, 1H), 4.76 (d,J=14 Hz, 1H), 4.77 (d, J=12.3 Hz, 1H), 5.33 (d, J=11.1 Hz, 1H), 5.35 (d,J=11.1 Hz, 1H), 7.02 (t, J=8.4 Hz, 6H), 7.22-7.29 (m, 8H), 7.75-7.99 (m,4H); MS (+ve ion mode): m/z 433 (M⁺+1). Yield: 72%

Preparation of Compound of Formula XXI

To a solution of Formula XX (4.62 mmoles) inheptane:toluene:tetrahydrofuran (4:1:1) was added a compound of FormulaIX (6.99 mmoles) and pivalic acid (4.768 mmoles). The mixture wasrefluxed with azeotropic removal of water for about 22 to 25 hours. Thereaction mixture was concentrated, ethyl acetate was added, and thereaction mixture was washed with sodium bicarbonate solution and brine,was dried over anhydrous sodium sulphate and was concentrated to givethe crude product. The crude product was purified on column (silica gel,100-200 mesh) using 7% ethyl acetate in hexane.

¹H NMR (CDCl₃, 300 MHz): δ 0.99-1.08 (m, 2H), 1.25 (s, 3H), 1.34 (s),1.43 (s, 9H), 1.96 (d, J=6 Hz, 6H), 1.58-1.63 (m, 2H), 2.21 (dd, J=158.6Hz, 1H), 2.37 (dd, J=15 & 9 Hz, 1H), 3.51 (sept, J=6 Hz), 3.65 (brs,1H), 3.75-3.85 (m, 1H), 4.00-4.25 (m, 2H), 5.03 (s, 2H), 6.83-7.25 (m,14H). MS (+ve ion mode): m/z 670 (M⁺+1). yield 74%

Preparation of Compound of Formula XXII

To a solution of a compound of Formula XXI (0.8 g) in methanol:dioxan(2:8) mixture was added 10% palladium carbon (50% wet, 60% w/w). Theresulting reaction mixture was hydrogenated at 40 psi for about 2.5hours. After the reaction was over, the reaction mixture was passedthrough celite and the resulting solution was concentrated under vacuumto give the required product, which was further used as such for nextstep.

¹H NMR (CDCl₃, 300 MHz): δ 0.95-1.05 (m, 1H), 1.21-1.28 (m, 1H), 1.28(s, 3H), 1.34 (s, 3H), 1.43 (s, 9H), 1.47 (d, J=7.1 Hz), 1.59-1.65 (m,2H), 2.22 (dd, J=15.2 & 6.1 Hz, 1H), 2.35 (dd, J=15.2 & 6.1 Hz, 1H),3.61-3.66 (m, 2H), 3.67-3.86 (m, 1H), 4.00-4.15 (m, 2H), 6.95 (t, I=9Hz, 2H), 7.06-7.15 (m, 7H) MS (+ve ion mode): m/z 586 (M⁺+1) Yield 76%

Preparation of Compound of Formula Xa: Path a

To a solution of a compound of Formula XXII (1 equiv) in benzene at 0°C. under argon, oxalyl chloride (2.0 equiv) is added dropwise. After theevolution of gas ceases, the reaction mixture is heated on oil bath at70° C. for 2 hours. The reaction mixture is evaporated to dryness. Theresidue is dissolved in benzene (dry) and is added at ambienttemperature to a solution of amine of Formula IIIa (1.1 equiv.) inpresence of triethylamine, in benzene. The reaction mixture is thenheated to 70° C. until completion of reaction. Volatiles are removed invacuo and the residue is purified on a chromatographic column (silicagel, 100-200 mesh).

Preparation of Compound of Formula Xa: Path b

To a solution of a compound of Formula XXII (1.2 mmole) indimethylformamide (2.5 ml) is added diisopropylethylamine (2.4 mmole)and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl uroniumhexafluorophosphate (HBTU) (1.2 mmoles). To the resulting clear solutionis then added cyclohexylamine (1.2 mmoles) in dimethylformamide (0.5ml). The reaction mixture is stirred at 50° C. to 60° C. overnight. Tothe reaction mixture is added water and the mixture is extracted withdichloromethane, the organic layer is washed with water, brine, is driedover anhydrous sodium sulphate and is concentrated to get the crudeproduct. The crude product is purified by column chromatography (silicagel, 100-200 mesh) using 10% ethyl acetate in hexane.

Preparation of Hemi Calcium Salt of Formula XIa

(a) To a solution of a compound of Formula Xa in methanol andtetrahydrofuran (1:1) is added 1N hydrochloric acid (3 equiv) and themixture is stirred at ambient temperature. After the complete hydrolysisof ketal, the reaction mixture is cooled to 0° C. and sodium hydroxidepellets (6 equiv) are added. The reaction is then stirred at ambienttemperature. At the end of ester hydrolysis, solvents are removed andthe residue is dissolved in water; the aqueous layer is washed withether, and is neutralized with 1N hydrochloric acid. The organics phaseis extracted into ethyl acetate, and concentrated. The residue is thenpurified on a chromatographic column (silica gel 100-200 mesh).

(b) To an aqueous solution of the sodium salt of the acid (is preparedby adding 1 equivalent 1N sodium hydroxide solution) is added dropwisean aqueous solution (1M) of calcium acetate (0.55 equiv). Whiteprecipitate is obtained, which is filtered, is washed with copiousamount of water, and is dried in vacuo. The following compounds can beprepared following scheme Ib or IIIa or both.

-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-acetoxymethylphenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    2a) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylthiocarbamoyloxyraethylphenyl)amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic    acid (Compound No. 3a) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-propionyloxymethylphenyl)amino)    carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 4a)    and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-octylcarbamoyloxymethyl    phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 5a) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylacetoxymethyl    phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 6a) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylcarbamoyloxymethyl    phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 7a) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzoyloxymethyl    phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 8a) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-isonicotinoyloxymethyl    phenyl)amino) carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 9a) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-pyridin-4-ylcarbamoyloxymethyl    phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 10a) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-phenylcarbamoyl    phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 11a) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-cyclohexylcarbamoyl-phenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    12a) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-methylcarbamoyl)-phenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    13a) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzylcarbamoyl)-phenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No.    14a) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(morpholine-4-carbonyl)-phenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 15) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(piperidine-1-carbonyl)-phenyl)amino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 16) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-benzylamino    phenyl)amino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 17) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(1-hydroxyethyl)phenylamino)    carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 18)    and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(2-hydroxyethyl)phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 19) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-hydroxypropyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 20) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methoxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 21) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-ethoxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 22) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-isopropoxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 23) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-propoxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 24) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-methoxymethoxymethylphenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 25) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-cyclohexyloxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 26) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-cyclopentyloxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 27) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzyloxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 28) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-chlorobenzyloxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 29) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4    methoxybenzyloxymethyl phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 30) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-phenoxymethylphenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 31) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-chlorophenoxymethyl    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 32) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-acetylaminophenylamino)    carbonyl]pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound No. 33)    and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzoylamino    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 34) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[(4-benzenesulfonylamino    phenylamino) carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid    (Compound No. 36) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-phenyl-ureido)-phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 37) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-methyl-ureido)-phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 38) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-benzyll-ureido)-phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 39) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-benzyl-thioureido)-phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 40) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-phenyl-thioureido)-phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 41) and its hemicalcium salt,-   (3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-(3-methyl-thioureido)-phenylamino)    carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid (Compound    No. 42) and its hemicalcium salt.

Pharmacological Activity

The compounds disclosed herein have activity as inhibitors of3-hydroxy-3-methyl-glutanyl coenzyme A (HMG-CoA) reductase, and thus areuseful in inhibiting cholesterol biosynthesis and/or in loweringtriglycerides.

The compounds described herein are screened in an in-vitro HMG-CoAreductase enzyme assay as described by Kubo et al., Endocrinology120:214 (1987) and Hellar et al., Biochem and Biophys. Res. Comm. 50:859(1973).

HMG-CoA reductase is a rate-limiting enzyme in the cholesterolbiosynthesis, catalyzing the following reaction.

[¹⁴C]HMG-CoA+2NADPH+2H⁺→[¹⁴C]mevanolate+CoA+2NADP⁺ microsomes, utilizing2.5 μM [¹⁴C]HMG-CoA as a substrate. The reaction is carried out inpresence of 100 mM KH₂PO₄, 20 mM G-6-P, 2.5 mM NADP, 10 mM EDTA, 5 mMDTT and 1.4 G-6-P dehydrogenase, at 37° C. for 15 minutes andquantitating [¹⁴C]mevalonate as an end product. For IC₅₀ determination,the compounds dissolved in 1% dimethylsulfoxide are preincubated withliver microsomes at 37° C. for 30 minutes.

The IC₅₀ for HMG-CoA reductase inhibition in rat liver microsome rangedfrom 0.1 to 0.96 nM. The compounds disclosed herein ranged from beingequipotent to 4 fold more potent than atorvastatin. Some of thecompounds disclosed herein were potent than atorvastatin in inhibitingcholesterol synthesis in vivo rat model. Some of the compounds disclosedherein have intrinsic clearance in human liver microsome significantlyless than atorvastatin and are not major substrate for CYP3A4(cytochrome p450 3A4). Some of the compounds exhibit potency andselectivity greater than atorvastatin in inhibition of cholesterolsynthesis in rat primary hepatocytes over inhibition of cholesterolsynthesis in extra hepatic cells/cell lines [e.g. NRK-49F (Fibroblast)and L6 (Myoblast)].

While the present invention has been described in terms of its specificembodiments, certain modifications and equivalents will be apparent tothose skilled in the art and are intended to be included within thescope of the present invention.

1. A compound of the structure of Formula Ib,

or a pharmaceutically acceptable salt thereof, pharmaceuticallyacceptable tautomer, racemate, pure enantiomer, diastereoisomer or alactone form or N-oxide thereof, wherein

R₁ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, or optionally substituted phenyl(wherein the substituent(s) is/are selected from halogens, C₁-C₆ alkyl,cyano and C₁-C₃ perfluoroalkyl); R₂ is optionally substituted phenyl(wherein the substituent(s) is/are selected from cyano, acetyl andoptionally substituted amino); R₃ is optionally substituted C₁-C₆ alkylor C₃-C₆ cycloalkyl (wherein the substituent(s) is/are selected fromhalogens, hydroxyl, C₁-C₃ alkoxy, and protected hydroxyl); R₃ can alsobe —NR₆R₇ wherein R₆ and R₇ are optionally substituted C₁-C₆ alkyl(wherein the optional substituent(s) is/are selected from halogens,hydroxyl, C₁-C₃ alkoxy, and protected hydroxyl); R₄ is —COR₁₀ (whereinR₁₀ is selected from C₁-C₂ alkoxy, hydroxyl and —NR₁₁R₁₂ (wherein R₁₁and R₁₂ are independently selected from hydrogen, alkyl, aryl, C₃-C₇cycloalkyl, aralkyl and R₁₁ and R₁₂ together form 5-7 membered ring withone or more optional heteroatom(s) wherein the heteroatom(s) is/areindependently selected from nitrogen, oxygen and sulphur); and R₅ ishydrogen, C₁-C₆ alkyl or C₃-C₆ cycloalkyl, optionally substituted arylor aralkyl [wherein the substituents are selected from halogens, cyano,optionally substituted C₁-C₆ alkyl (wherein the substituents areindependently selected from hydroxyl, protected hydroxyl, andhalogen(s)], optionally substituted amino, acetyl, trifluoromethyl andC₁-C₆ alkoxycarbonyl.
 2. The compound of claim 1 wherein R1, R2, R3 andR5 are 4-fluorophenyl, phenyl, isopropyl and hydrogen, respectively. 3.The compound according to claim 1, wherein R1 is phenyl substituted withone or more halogen.
 4. The compound according to claim 3, wherein R1 isphenyl substituted with one or more fluorine.
 5. The compound accordingto claim 4, wherein R1 is 4-fluorophenyl.
 6. The compound according toclaim 1, wherein R2 and R5 are phenyl and hydrogen, respectively.
 7. Thecompound according to claim 1, wherein R3 is C1-C6 alkyl.
 8. Thecompound according to claim 1, wherein R3 is isopropyl.
 9. The compoundaccording to claim 1, wherein R10 is hydroxyl.
 10. A compound accordingto claim 1, wherein R3 is alkyl of from one to six carbon atoms orcycloalkyl of from three to six carbon atoms.
 11. A compound of thechemical formula:

wherein

or a pharmaceutically acceptable salt thereof.
 12. A compound, which is(3R,5R)-7-[2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4-[4-carboxyphenyl)amino)carbonyl]-pyrrol-1-yl]-3,5-dihydroxy-heptanoic acid or apharmaceutically acceptable salt thereof.
 13. A pharmaceuticallyacceptable salt of a compound of claim 1, wherein the salt is selectedfrom the group consisting of lithium, sodium, potassium, calcium,magnesium, zinc, aluminium, amino acid, ammonium, mono-alkyl ammonium,dialkyl ammonium, trialkyl ammonium and N-methyl glucamine.
 14. Thepharmaceutically acceptable salt of claim 13, wherein the salt is sodiumsalt.
 15. The pharmaceutically acceptable salt of claim 13, wherein thesalt is potassium salt.
 16. The pharmaceutically acceptable salt ofclaim 13, wherein the salt is hemicalcium salt.
 17. The pharmaceuticallyacceptable salt of claim 13, wherein the salt is hemimagnesium salt. 18.The pharmaceutically acceptable salt of claim 13, wherein the salt ishemizinc salt.
 19. The pharmaceutically acceptable salt of claim 13,wherein the salt is N-methyl glucamine salt.
 20. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 together with a pharmaceutically acceptable carrier,excipient or diluent.
 21. A method of treating diabetes or a diseaseselected from the group consisting of arteriosclerosis, atherosclerosis,hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia,hypertriglyceridemia, hypertension, stroke, ischemia, peripheralvascular disease, peripheral arterial disease, coronary heart disease,myocardial infarction, cerebral infarction, myocardial microvasculardisease, dementia, Alzheimer's disease, angina and restenosis in amammal in need of such treatment comprising administering atherapeutically-effective amount of a compound of claim 1 to the mammal.22. The method according to claim 21, wherein the disease ishyperlipidemia.
 23. The method according to claim 21, wherein thedisease is hypercholesterolemia.
 24. The method according to claim 21,wherein the disease is hyperlipoproteinemia.
 25. The method according toclaim 21, wherein the disease is hypertriglyceridemia.
 26. The methodaccording to claim 21, wherein the disease is hypertension.